CN103189363B - Aryltriazolin (ethi) ones that two aryl connects and uses thereof - Google Patents

Aryltriazolin (ethi) ones that two aryl connects and uses thereof Download PDF

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CN103189363B
CN103189363B CN201180021341.1A CN201180021341A CN103189363B CN 103189363 B CN103189363 B CN 103189363B CN 201180021341 A CN201180021341 A CN 201180021341A CN 103189363 B CN103189363 B CN 103189363B
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CN103189363A (en
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C.菲尔施特纳
J.克尔德尼希
M.德尔贝克
P.科尔克霍夫
A.克雷奇默
I.普卢施克尔
E.波克
C.施梅克
H.特吕贝尔
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Bayer Pharma AG
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Abstract

The application relates to the 5-aryl-1 that new two aryl connect, 2,4-triazolone derivative, they preparation method, they are used for the treatment of and/or prophylactic purposes and they are for the production of the purposes of medicine either individually or in combination, described medicine is used for the treatment of and/or preventing disease, especially for treating and/or preventing cardiovascular disorder.

Description

Aryltriazolin (ethi) ones that two aryl connects and uses thereof
The application relates to the 5-aryl-1 that novel two aryl connect, 2,4-triazolone derivative, they preparation method, they are used for the treatment of either individually or in combination and/or prophylactic purposes and they are for the production of the purposes of medicine, described medicine is used for the treatment of and/or preventing disease, especially for treating and/or preventing cardiovascular disorder.
The content liquid of human body determined by different physiology control mechanisms, its objective is constant (volume homeostasis) that keep it.Here, the volume fill-up (Volumenf ü llung) of vascular system and the perviousness of blood plasma are by corresponding susceptor (pressure receptor and osmoreceptor) record continuously.The information that these susceptors transmit to the supervisor center of brain regulates drinking behavior and by means of body fluid signaling and the Control neural signal fluid drainage via kidney.Peptide hormone vassopressin plays an important role wherein [Schrier R.W., Abraham, W.T., new Engl. J. Med. 341, 577-585(1999)].
Vassopressin is produced by the internal secretion neurone of the nucleus supraopticus in the wall of third ventricle (hypothalamus) and the specialization in paraventricular nucleus, and is sent in neurohypophysis (neurohypophysis) along described neuronic spinous process therefrom.There, this hormone is discharged in blood circulation according to stimulation.Capacitance loss (such as due to acute hemorrhage, a large amount of perspiration, for a long time thirsty or diarrhoea) is the stimulus that this hormone flows out in a large number.On the contrary, the increase (such as due to the increase of liquid absorption) of intravasal volume suppresses the secretion of vassopressin.
Vassopressin is mainly through playing its effect with the combination of 3 kinds of acceptors, and described acceptor is classified as V1a-, V1b-and V2-acceptor, and belongs to g protein coupled receptor family.V1a acceptor is mainly positioned on the cell of vascular smooth muscle tissue.Their activation causes vasoconstriction, thus raises Peripheral resistance and blood pressure.In addition, in liver, also V1a acceptor can be detected.V1b acceptor (also referred to as V3 acceptor) can be detected in central nervous system.Together with corticotropin-releasing hormone (CRH), vassopressin via V1b regulation thyroliberin (ACTH) basis with the secretion of stress-induced.V2 acceptor is arranged in the epithelium of distal tubular epithelium and kidney collecting tubule.Their activation makes these epitheliums can pass through water.This phenomenon is owing to embedded in aquaporin (special aquaporin) in the film of epithelial chamber.
Which kind of importance vassopressin has for the heavily absorption from the water in the urine in kidney, becomes obvious by the illness of the diabetes insipidus caused due to hormonoprivia (such as due to pituitary body damage).If do not use alternative hormone to them, suffer the patient of this illness every 24 hours maximum 20 liters of urine of excretion.This volume is equivalent to the crude urine of about 10%.Because it is for the huge importance heavily absorbed from urine for water, vassopressin is also synonymously called antidiuretic hormone (ADH).Logically, the homaluria increased can be caused to the pharmacology suppression of the vassopressin/ADH effect of V2 acceptor.But contrary with the effect of other diuretic(s) (thiazides and loop diuretic(s) class), V2 receptor antagonist causes the water of increase to drain, and significantly do not increase electrolytical excretion.This means, by V2 agonist drug, can volume homeostasis be recovered, and not affect electrolyte body homeostasis at this.Therefore, the medicine playing V2 antagonistic action seems to be particularly suitable for the water for the treatment of with health and transships, and all morbid states that corresponding increase ionogen is not relevant simultaneously.In clinical chemistry, significant ionogen extremely can be used as hyponatremia (na concn < 135 mmol/L) and records; It is that most important ionogen is abnormal in inpatient, only has the frequent degree of about 5% or annual 250000 examples in the U.S..When plasma sodium concentration drops to 115 below mmol/L, then face comatose state and death.
According to basic reason, divide into hypovolemic, Q volume of blood is normal and hypervolemic hyponatremia.Importantly there is hypervolemic form that oedema is formed clinically.Representative instance is for this reason that the syndrome of unsuitable ADH/ inappropriate secretion (SIAD) is (such as after craniocerebral injury, or as the tumour of cancer with disease) and the hypervolemic hyponatremia [people such as De Luca L. in liver cirrhosis, multiple kidney diaseases and heart failure am. J. Cardiol. 96(supplementary issue), 19L-23L(2005)].Particularly, although the hyponatremia that they are relative and hypervolemia, suffer from and have the vasopressin levels that patient in heart failure often shows rising, this is considered the consequence [people such as Francis G.S. of neuron soma fluidity adjustment of general multilated in heart failure circulation 82, 1724-1729(1990)].
The neuron soma fluidity of multilated regulates and is mainly manifested in the rising of sympathetic tone and the inappropriate activation of renin-angiotensin-aldosterone system.Now, the intrinsic part of pharmacological treatment in heart failure suppresses these components by beta-blocker and another aspect by ACE inhibitor or Angiotensin-receptor-blocking agent on the one hand, at present, but in heart failure, the inappropriate rising of inappropriate secretion remains and can not fully treat late.Except by the receptor-mediated water of V2 reservation and relevant with it increase in (Nachlasterh hung) except disadvantageous Hemodynamics consequence at afterload, the pressure in emptying, the Pulmonary Vascular of left ventricle and heart power are also subject to the vasoconstrictive disadvantageous effect of V1a mediation.In addition, based on animal experimental data, to the direct plump promoter action of cardiac muscle also owing to vassopressin.Different from the effect (it is mediated by the activation of V2 acceptor) of the volume expansion of kidney, this direct effect of cardiac muscle is triggered by the activation of V1a acceptor.
For these reasons, vassopressin is suppressed to seem that to be applicable to treatment in heart failure to V2 and/or to the material of the effect of V1a acceptor.First, have to be combined with and should wish all to work to kidney effect and haemodynamic effect to the compound of the activity of two kinds of vasopressin receptors (V1a and V2), and thus provide for the treatment for the treatment of heart failure patient characteristic desirable especially.The vasopressin antagonists of such combination is provided also to seem it is rational on this point, because the capacity minimizing mediated separately via V2 receptor block can cause the stimulation of osmoreceptor, and the further compensatory increase therefore causing vassopressin to discharge.As a result, lacking under the component simultaneously blocking V1a acceptor exists, can the deleterious effect of strengthening vassopressin further, such as vasoconstriction and myocardial hypertrophy [people such as Saghi P., europ. Heart J. 26, 538-543(2005)].
Therefore, the object of the invention is, provide new compound, described compound works as effective selectivity or dual V1a/V2 receptor antagonist, and be applicable to treat and/or prevent disease as such antagonist, especially for treating and/or preventing cardiovascular disorder.
4-(alkyl diphenyl)-1,2, the 4-triazolone with Angiotensin II-antagonistic action being used for the treatment of cardiovascular disorder is described in EP 0 412 594-A2, WO 92/20662-A1 and US 2001/0020100-A1.Claimed 1,2, the 4-triazolone of dissimilar replacement as can be used for the integrain receptor antagaonists for the treatment of in WO 99/31099-A1.In WO 99/54315-A2, disclose 5-aryl-1,2,4-triazolone as the purposes of medicine with neuroprotective, and in WO 2006/117657-A1, describe 4, the 5-diaryl triazolone derivatives as antiphlogiston.The claimed different heterogeneous ring compound as tyrosine phosphatase inhibitors being used for the treatment of diabetes in WO 2006/078698-A1.In WO 2005/105779-A1, disclose the 3-heterocyclic radical-4-Phenyltriazole of the inhibitor as vassopressin V1A acceptor, and in WO 2007/134862-A1, describe 5-aryl-1,2, the 4-triazolone be connected as the acid amides of dual vasopressin antagonists.By Benzoylpyrazols and the benzoyl isooxazole of the known heterocyclic substituted as weedicide of WO 00/58306-A1 and WO 00/68227-A1.
Theme of the present invention is the compound of general formula (I) and the solvate of their salt, solvate and described salt:
Wherein
R 1represent (C 1-C 6)-alkyl, (C 2-C 6)-thiazolinyl or (C 2-C 6)-alkynyl, each in them all can be selected from following identical or different residue Dan Zhisan and replace: fluorine, chlorine, cyano group, trifluoromethyl, oxo, hydroxyl, difluoro-methoxy, trifluoromethoxy, (C 1-C 4)-alkoxyl group, (C 3-C 7)-cycloalkyl and phenyl,
Wherein (C 3-C 7)-cycloalkyl can be selected from following identical or different residue and replace maximum 2 times: fluorine, trifluoromethyl, (C 1-C 4)-alkyl, oxo, hydroxyl, trifluoromethoxy and (C 1-C 4)-alkoxyl group,
And
Wherein phenyl can be selected from maximum 3 times of following identical or different residue replacement: halogen, cyano group, nitro, difluoromethyl, trifluoromethyl, (C 1-C 4)-alkyl, hydroxyl, methylol, difluoro-methoxy, trifluoromethoxy, (C 1-C 4)-alkoxyl group, (C 1-C 4)-alkoxy methyl, hydroxycarbonyl group, (C 1-C 4)-alkoxy carbonyl, aminocarboxyl, list-(C 1-C 4)-alkyl amino-carbonyl and two-(C 1-C 4)-alkyl amino-carbonyl,
Or
Represent (C 3-C 7)-cycloalkyl, it can be selected from following identical or different residue list or two replacements: fluorine, trifluoromethyl, (C 1-C 4)-alkyl, oxo, hydroxyl, trifluoromethoxy and (C 1-C 4)-alkoxyl group,
Ar 1represent phenyl, thienyl or furyl, each in them all can be selected from following identical or different residue Dan Zhisan and replace: halogen, cyano group, nitro, difluoromethyl, trifluoromethyl, (C 1-C 4)-alkyl, hydroxyl, trifluoromethoxy and (C 1-C 4)-alkoxyl group,
L 1represent group-CH 2-,-C (=O)-or-SO 2-,
Q represents phenyl ring, have maximum 3 is selected from ring-heteroatomic 5 yuan of hetero-aromatic rings of N, O and/or S or has 6 yuan of hetero-aromatic rings of maximum 3 ring-nitrogen-atoms,
R 2represent and be selected from following substituting group: fluorine, chlorine, bromine, cyano group, nitro, (C 1-C 4)-alkyl, (C 3-C 6)-cycloalkyl, phenyl, hydroxyl, (C 1-C 4)-alkoxyl group, amino, amino carbonyl amino, (C 1-C 4)-alkyl-carbonyl-amino, hydroxycarbonyl group, (C 1-C 4)-alkoxy carbonyl, aminocarboxyl, list-(C 1-C 4)-alkyl amino-carbonyl and two-(C 1-C 4)-alkyl amino-carbonyl,
Wherein with regard to described (C 1-C 4)-alkyl substituent, can by hydroxyl, (C 1-C 4)-alkoxyl group, carbamoyloxy group, hydroxycarbonyl group, (C 1-C 4)-alkoxy carbonyl, aminocarboxyl, list-(C 1-C 4)-alkyl amino-carbonyl or two-(C 1-C 4)-alkyl amino-carbonyl replaces, or replaced by fluorine maximum 3 times,
And
Wherein with regard to described phenyl substituent, can by fluorine, chlorine, cyano group, methyl, trifluoromethyl or methoxy substitution,
N representative digit 0,1 or 2,
Wherein in substituent R 2when occurring 2 times, its implication can be identical or different,
L 2represent key, expression-O-or expression-(CR 3Ar 3B) p-group, wherein
R 3Arepresent hydrogen, fluorine or methyl,
R 3Brepresent hydrogen, fluorine, (C 1-C 4)-alkyl, hydroxycarbonyl group, (C 1-C 4)-alkoxy carbonyl or aminocarboxyl,
Wherein (C 1-C 4)-alkyl can be replaced by hydroxyl or carbamoyloxy group, or replaced by fluorine maximum 3 times,
Or
R 3Aand R 3Bbe connected with each other and common formation-(CH 2) rbridge, wherein
R representative digit 2,3,4 or 5,
And the CH of this bridge 2group can be substituted by-O-,
And
P representative digit 1 or 2,
Wherein at group-CR 3Ar 3B-occur 2 times when, R 3Aand R 3Bimplication respective in each case can be identical or different,
And
Ar 2represent phenyl, naphthyl or have maximum 3 rings being selected from N, O and/or S-heteroatomic 5-10 unit heteroaryl, each in them all can be selected from following identical or different residue Dan Zhisan and replace: halogen, cyano group, nitro, difluoromethyl, trifluoromethyl, (C 1-C 4)-alkyl, hydroxyl, difluoro-methoxy, trifluoromethoxy and (C 1-C 4)-alkoxyl group.
Compound according to the present invention is the solvate of formula (I) compound and their salt, solvate and described salt; The compound of the formula mentioned below being comprised by formula (I) and the solvate of their salt, solvate and described salt; And the solvate of the compound comprised by formula (I) mentioned as working Examples below and their salt, solvate and described salt; As long as by mentioning below of comprising of formula (I) is not also the compound of the solvate of salt, solvate and described salt.
Depend on their structure, can exist with different stereoisomeric forms in any ratio according to compound of the present invention, namely exist with the form of configurational isomer, or also may exist as conformer (enantiomer and/or diastereomer, when being included in atropisomer those).Therefore the present invention comprises enantiomer and diastereomer and their often kind of mixture.In known manner, the consistent composition of stereoisomerism can be isolated from such mixture of enantiomer and/or diastereomer; Preferably use chromatography, especially in the HPLC chromatography that achirality or chirality are gone up mutually for this reason.
If can exist with tautomeric form according to compound of the present invention, then the present invention includes all tautomeric forms.
The present invention also comprises all suitable isotopic variations according to compound of the present invention.Here be interpreted as according to the isotopic variations of compound of the present invention and refer to such compound: wherein at least one atom has been replaced by another atom of same atoms ordinal number in compound according to the present invention, but described another monatomic atomic mass is different from the atomic mass that occurring in nature exists usually or advantage exists.Can mix and according to the isotopic example in compound of the present invention be: the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as 2h(deuterium), 3h(tritium), 13c, 14c, 15n, 17o, 18o, 32p, 33p, 33s, 34s, 35s, 36s, 18f, 36cl, 82br, 123i, 124i, 129i and 131i.According to some isotopic variations of compound of the present invention (as particularly wherein mixed one or more radioisotopic those) may be useful, such as, for checking the mechanism of action in vivo or active substance distribution in vivo; Owing to being comparatively speaking easy to the property prepared and detectability, use 3h-or 14the isotope-labeled special compound of C-is applicable to this object.In addition, due to the more greater metabolic stability of compound, mixing of isotropic substance (such as deuterium) can cause certain treatment benefit, such as, cause the prolongation of Half-life in vivo or cause the reduction of required active dose; Therefore, also optionally the preferred embodiment of the present invention can be formed according to this modification of compound of the present invention.By universal method well known by persons skilled in the art, such as according to the method be described below and the method described in working Examples, by using the corresponding isotropic substance modification of respective reaction reagent and/or initial compounds wherein, the isotopic variations according to compound of the present invention can be prepared.
As salt, the preferred within the scope of the present invention physiologically acceptable salt according to compound of the present invention.Also comprise such salt: although itself be not suitable for medicinal, its can such as separating of, purifying or storage according to compound of the present invention.
Comprise the acid salt of mineral acid, carboxylic acid and sulfonic acid according to the physiologically acceptable salt of compound of the present invention, example is hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, ethyl sulfonic acid, toluenesulphonic acids, Phenylsulfonic acid, naphthalene disulfonic acid, acetic acid, trifluoracetic acid, propionic acid, lactic acid, grape acid, oxysuccinic acid, citric acid, fumaric acid, toxilic acid and benzoic salt.
Also the salt of conventional alkali is comprised according to the physiologically acceptable salt of compound of the present invention, such as and preferably, an alkali metal salt (such as sodium salt and sylvite), alkaline earth salt (such as calcium salt and magnesium salts) and ammonium salt, its be derived from ammonia or be derived from there is 1-16 C atom organic amine such as and preferably, ethamine, diethylamine, triethylamine, n,N-diisopropylethylamine, monoethanolamine, diethanolamine, trolamine, dimethylaminoethanol, diethylaminoethanol, PROCAINE HCL, PHARMA GRADE, dicyclohexyl amine, dibenzylamine, n-methyl piperidine, n-methylmorpholine, arginine, Methionin and 1，2-diaminoethane.
Within the scope of the present invention, solvate refers to the such form according to compound of the present invention: its with solid or liquid state by forming complex compound with the coordination of solvent molecule.Hydrate is a kind of specific form of solvate, and wherein said coordination occurs with water.As solvate preferably water compound within the scope of the present invention.
In addition, the present invention also comprises the prodrug according to compound of the present invention.At this, term " prodrug " represents such compound: himself can be biologically activated or non-activity, but during their residence time in vivo, it is converted (such as, metabolism or hydrolysis) becomes according to compound of the present invention.
Within the scope of the present invention, unless otherwise noted, described substituting group has following definitions:
Within the scope of the present invention, (C 1-C 6)-alkyl and (C 1-C 4alkyl residue that is that)-alkyl represents the straight chain with 1-6 and 1-4 carbon atom respectively or side chain.Preferably have the straight chain of 1-4 carbon atom or side chain alkyl residue.Such as and preferably, can mention: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, 2-amyl group, 3-amyl group, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl.
Within the scope of the present invention, (C 1-C 4alkyl residue that is that)-alkyl-carbonyl represents the straight chain with 1-4 carbon atom or side chain, described alkyl group is connected with the remainder of described molecule via carbonyl [-C (=O)-].Such as and preferably, can mention: ethanoyl, propionyl, positive butyryl radicals, isobutyryl, positive pentanoyl and valeryl.
Within the scope of the present invention, (C 2-C 6alkenyl residue that is that)-thiazolinyl represents the straight chain with 2-6 carbon atom and a double bond or side chain.Preferably have the straight chain of 3-6 carbon atom or side chain alkenyl residue.Such as and preferably, can mention: vinyl, positive third-1-alkene-1-base, allyl group, pseudoallyl, 2-methyl-2-propylene-1-base, positive but-1-ene-1-base, positive but-2-ene-1-base, positive fourth-3-alkene-1-base, positive penta-2-alkene-1-base, positive penta-3-alkene-1-base, positive penta-4-alkene-1-base, 3-methyl but-2-ene-1-base and 4-methylpent-3-alkene-1-base.
Within the scope of the present invention, (C 2-C 6alkynyl residue that is that)-alkynyl represents the straight chain with 2-6 carbon atom and a triple bond or side chain.Preferably have the straight chain of 3-6 carbon atom or side chain alkynyl residue.Such as and preferably, can mention: ethynyl, positive third-1-alkynes-1-base, positive third-2-alkynes-1-base, positive fourth-2-alkynes-1-base, positive fourth-3-alkynes-1-base, positive penta-2-alkynes-1-base, positive penta-3-alkynes-1-base and positive penta-4-alkynes-1-base.
Within the scope of the present invention, (C 1-C 4alkoxy residue that is that)-alkoxyl group represents the straight chain with 1-4 carbon atom or side chain.Such as and preferably, can mention: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.
Within the scope of the present invention, (C 1-C 4alkoxy residue that is that)-(alkoxymethyl)-2 basis representation has a straight chain of 1-4 carbon atom or side chain, described alkoxy residue is via the methylene radical [-CH be connected with Sauerstoffatom 2-] be connected with the remainder of described molecule.Such as and preferably, can mention: methoxymethyl, ethoxyl methyl, n-propoxymethyl, i-propoxymethyl, n-butoxy methyl and t-butoxymethyl.
Within the scope of the present invention, (C 1-C 4alkoxy residue that is that)-alkoxy carbonyl represents the straight chain with 1-4 carbon atom or side chain, described alkoxy residue is connected with the remainder of described molecule via the carbonyl be connected with Sauerstoffatom [-C (=O)-].Such as and preferably, can mention: methoxycarbonyl, ethoxy carbonyl, positive propoxy carbonyl, isopropoxy carbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.
Within the scope of the present invention, list-(C 1-C 4)-alkylamino represents such amino group: alkyl substituent that is that it has a straight chain containing 1-4 carbon atom or side chain.Such as and preferably, can mention: methylamino-, ethylamino, n-propyl amino, isopropylamino, n-butylamino and tert-butylamino.
Within the scope of the present invention, two-(C 1-C 4)-alkylamino represents the amino group of alkyl substituent that is that have 2 identical or different straight chains or side chain, and described alkyl substituent respectively has 1-4 carbon atom.Such as and preferably, can mention: n,N-dimethylamino, n,N-diethylin, n-ethyl- n-methylamino, n-methyl- n-n-propyl amino, n-sec.-propyl- n-methylamino, n-sec.-propyl- n-n-propyl amino, n,N-diisopropylaminoethyl, n-normal-butyl- n-methylamino, n,N-di-n-butyl amino and n-tertiary butyl- n-methylamino.
Within the scope of the present invention, list-and two-(C 1-C 4the amino group that)-alkyl amino carbonyl basis representation is such: it is connected with the remainder of described molecule via carbonyl [-C (=O)-], and there is 1 straight chain or side chain and 2 identical or different straight chains or side chain n-alkyl substituent, described in n-alkyl substituent respectively has 1-4 carbon atom.Such as and preferably, can mention: amino-carbonyl, B aminocarbonyl, n-propyl aminocarboxyl, isopropylaminocarbonyl, n-butylaminocarbonyl, tert-butylamino carbonyl, n,N-dimethyl-aminocarbonyl, n,N-diethylaminocarbonyl-, n-ethyl- n-methylaminocarbonyl, n-methyl- n-n-propyl aminocarboxyl, n,N-diisopropylaminoethyl carbonyl, n-normal-butyl- n-methylaminocarbonyl and n-tertiary butyl- n-methylaminocarbonyl.
Within the scope of the present invention, (C 1-C 4)-alkyl-carbonyl-amino represents the amino group of alkylcarbonyl substituents that is that have a straight chain or side chain, and it has 1-4 carbon atom in alkyl group, and is connected with atom N via carbonyl.Such as and preferably, can mention: acetylamino, propanoylamino, positive butyryl radicals amino, isobutyrylamino, positive pentanoylamino and valeryl amino.
Within the scope of the present invention, (C 3-C 7)-cycloalkyl and (C 3-C 6)-cycloalkyl represents the saturated cyclic alkyls of the monocycle with 3-7 and 3-6 carbon atom respectively.Preferably there is the cycloalkyl residues of 3-6 carbon atom.Such as and preferably, can mention: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl.
5 yuan of heteroaryls in ring Q defines represent such aromatic heterocycle (heteroaromatic): it has totally 5 annular atomses, and containing maximum 3 identical or different ring-heteroatomss being selected from N, O and/or S, and be connected via ring-carbon atom or possible ring-nitrogen-atoms.As an example, can mention: furyl, pyrryl, thienyl, pyrazolyl, imidazolyl, 1,2-oxazolyl (isoxazolyl), 1,3-oxazolyl, 1,2-thiazolyl (isothiazolyl), 1,3-thiazoles base, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl group and 1,3,4-thiadiazolyl group.
6 yuan of heteroaryls in ring Q defines represent the aromatic heterocycle (heteroaromatic) with 6 annular atomses altogether, and it contains 1,2 or 3 ring-nitrogen-atoms, and are connected via ring-carbon atom.As an example, can mention: pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, 1,2,4-triazinyl and 1,3,5-triazines base.Preferably there are 6 yuan of heteroaryls of 1 or 2 ring-nitrogen-atoms, such as pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.
Within the scope of the present invention, 5-10 unit heteroaryl represents such monocycle or optional bicyclic aromatic heterocycle (heteroaromatic): it has 5-10 annular atoms altogether, described annular atoms contains maximum 3 ring-heteroatomss being selected from N, O and/or S, and it is connected via ring-carbon atom or possible ring-nitrogen-atoms.As an example, can mention: furyl, pyrryl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl group, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuryl, benzothienyl, benzimidazolyl-, benzoxazolyl, benzothiazolyl, benzotriazole base, indyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolyl, quinoxalinyl, phthalazinyl, pyrazolo [3,4-b] pyridyl.Preferably there are maximum 2 and be selected from the heteroatomic monocycle of N, O and/or S or two optional ring 5-10 unit heteroaryl residue.Particularly preferably there are maximum 2 5-or 6 yuan heteroaryl residue being selected from the heteroatomic monocycle of N, O and/or S, such as, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl.
Within the scope of the present invention, halogen comprises fluorine, chlorine, bromine and iodine.Preferred chlorine, fluorine or bromine, particularly preferably fluorine or chlorine.
Within the scope of the present invention, oxo substituent represents the Sauerstoffatom be connected with carbon atom by double bond.
Within the scope of the present invention, for all residues repeatedly occurred, its meaning is all independent of one another.If the residue in compound according to the present invention is substituted, then except as otherwise noted, described residue can by monosubstituted or polysubstituted.Preferably with 1 or the replacement carried out with 2 or 3 identical or different substituting groups.Particularly preferably with 1 or the replacement carried out with 2 identical or different substituting groups.The most particularly preferably with the replacement that 1 substituting group carries out.
Within the scope of the present invention, the compound of preferred formula (I) and the solvate of their salt, solvate and described salt, wherein
R 1represent (C 1-C 6)-alkyl, it can be selected from following identical or different residue Dan Zhisan and replace: fluorine, trifluoromethyl, oxo, hydroxyl, methoxyl group, oxyethyl group, (C 3-C 6)-cycloalkyl and phenyl,
Wherein (C 3-C 6)-cycloalkyl can be selected from following identical or different residue and replace maximum 2 times: fluorine, methyl, trifluoromethyl, ethyl and hydroxyl
And
Wherein phenyl can be selected from maximum 2 times of following identical or different residue replacement: fluorine, chlorine, cyano group, methyl, difluoromethyl, trifluoromethyl, ethyl, hydroxyl, methoxyl group, trifluoromethoxy, oxyethyl group, hydroxycarbonyl group, methoxycarbonyl, ethoxy carbonyl and aminocarboxyl
Or
Represent (C 2-C 6)-thiazolinyl
Or
Represent (C 3-C 6)-cycloalkyl, it can be selected from following identical or different residue list or two replacements: fluorine, methyl, trifluoromethyl, ethyl and hydroxyl,
Ar 1represent phenyl or thienyl, they can be selected from following identical or different residue list or two replacements separately: fluorine, chlorine, cyano group, methyl, trifluoromethyl, ethyl, hydroxyl, methoxyl group, trifluoromethoxy and oxyethyl group,
L 1represent group-CH 2-or-SO 2-,
Q represents benzyl ring, have maximum 3 is selected from ring-heteroatomic 5 yuan of heteroaryl rings of N, O and/or S or has 6 yuan of heteroaryl rings of maximum 2 ring-nitrogen-atoms,
R 2represent and be selected from following substituting group: fluorine, chlorine, bromine, (C 1-C 4)-alkyl, (C 3-C 6)-cycloalkyl, phenyl, (C 1-C 4)-alkoxyl group, hydroxycarbonyl group, (C 1-C 4)-alkoxy carbonyl, aminocarboxyl and list-(C 1-C 4)-alkyl amino-carbonyl,
Wherein with regard to described (C 1-C 4)-alkyl substituent, can by hydroxyl, (C 1-C 4)-alkoxyl group, carbamoyloxy group, hydroxycarbonyl group, (C 1-C 4)-alkoxy carbonyl or aminocarboxyl replace, or replaced by fluorine maximum 3 times
And
Wherein with regard to described phenyl substituent, can be replaced by fluorine, chlorine, methyl or trifluoromethyl,
N representative digit 0 or 1,
L 2represent key or expression-(CR 3Ar 3B) p-group, wherein
R 3Arepresent hydrogen or methyl,
R 3Brepresent hydrogen, (C 1-C 4)-alkyl, hydroxycarbonyl group, (C 1-C 4)-alkoxy carbonyl or aminocarboxyl,
Wherein (C 1-C 4)-alkyl can be replaced by hydroxyl or carbamoyloxy group,
And
P representative digit 1 or 2,
Wherein at group-CR 3Ar 3B-occur 2 times when, R 3Aand R 3Bimplication respective in each case can be identical or different,
And
Ar 2represent phenyl, it can be selected from following identical or different residue list or two replacements: fluorine, chlorine, cyano group, difluoromethyl, trifluoromethyl, (C 1-C 4)-alkyl, methoxyl group, difluoro-methoxy, trifluoromethoxy and oxyethyl group.
A specific embodiment of the present invention comprises the solvate of such formula (I) compound and their salt, solvate and described salt, wherein
R 1represent (C 1-C 4)-alkyl, it can be selected from following identical or different residue list or two replacements: fluorine, trifluoromethyl, oxo and hydroxyl, or represents allyl group or cyclopropyl.
Another embodiment of the present invention comprises the solvate of such formula (I) compound and their salt, solvate and described salt, wherein
Ar 1represent phenyl or thienyl, it is selected from following residue separately and replaces: fluorine, chlorine, cyano group, methyl, trifluoromethyl, ethyl, hydroxyl, methoxyl group, trifluoromethoxy and oxyethyl group.
Another embodiment of the present invention comprises the solvate of such formula (I) compound and their salt, solvate and described salt, wherein
Ar 2represent phenyl, described phenyl is selected from following identical or different residue list or two replacements: fluorine, chlorine, cyano group, difluoromethyl, trifluoromethyl, (C 1-C 4)-alkyl, methoxyl group, difluoro-methoxy, trifluoromethoxy and oxyethyl group.
Another embodiment of the present invention comprises the solvate of such formula (I) compound and their salt, solvate and described salt, wherein
Q represents the benzyl ring of the optional replacement of following formula
Wherein
* represent and group L 1link position,
And
* represents and group L 2link position,
And
R 2Arepresent hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, methylol, carbamoyloxy group methyl, hydroxycarbonyl group, methoxycarbonyl, ethoxy carbonyl, aminocarboxyl, amino-carbonyl or tert-butylamino carbonyl.
Another embodiment of the present invention comprises the solvate of such formula (I) compound and their salt, solvate and described salt, wherein
Q represents pyridyl ring or the pyrimidine-ring of following formula
Wherein
* represent and group L 1link position,
And
* represents and group L 2link position.
Another embodiment of the present invention comprises the solvate of such formula (I) compound and their salt, solvate and described salt, wherein
Q represents 5 yuan of heteroaryl rings of the optional replacement of following formula
Wherein
* represent and group L 1link position,
And
* represents and group L 2link position,
R 2Brepresent hydrogen, methyl or trifluoromethyl,
And
R 2Crepresent hydrogen or methyl, described methyl can be replaced by hydroxycarbonyl group, methoxycarbonyl or aminocarboxyl.
Within the scope of the present invention, the solvate of particularly preferably such formula (I) compound and their salt, solvate and described salt, wherein
R 1represent (C 1-C 4)-alkyl, it can be selected from following identical or different residue list or two replacements: fluorine, trifluoromethyl, oxo, hydroxyl and phenyl,
Wherein with regard to phenyl, following group can be selected from and replace: fluorine, chlorine, methyl, trifluoromethyl, methoxyl group, hydroxycarbonyl group and methoxycarbonyl,
Or
Represent allyl group or cyclopropyl,
Ar 1represent phenyl or thienyl, they are selected from following group separately and replace: fluorine and chlorine,
L 1represent group-CH 2-,
Q represents the pyridyl ring of following formula, pyrimidine-ring or the optional benzyl ring replaced
Or
Represent 5 yuan of heteroaryl rings of the optional replacement of following formula
Wherein
* represent and group L 1link position,
And
* represents and group L 2link position,
R 2Arepresent hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, hydroxymethyl, carbamoyloxy group methyl, hydroxycarbonyl group, methoxycarbonyl, ethoxy carbonyl, aminocarboxyl, amino-carbonyl or tert-butylamino carbonyl,
R 2Brepresent hydrogen, methyl or trifluoromethyl
And
R 2Crepresent hydrogen or methyl, described methyl can be replaced by hydroxycarbonyl group, methoxycarbonyl or aminocarboxyl,
L 2represent key or group-CH 2-
And
Ar 2represent phenyl, described phenyl is selected from following identical or different residue list or two replacements: fluorine, chlorine, methyl, trifluoromethyl, methoxyl group and trifluoromethoxy.
Within the scope of the present invention, the solvate of the most such formula (I) compound and their salt, solvate and described salt, wherein
R 1represent (C 1-C 4)-alkyl, it can be selected from following identical or different residue list or two replacements: fluorine, trifluoromethyl and hydroxyl, or representative ring propyl group,
Ar 1represent rubigan,
L 1represent group-CH 2-,
Q represents the pyrimidine-ring of following formula
Or
Represent 5 yuan of heteroaryl rings of the optional replacement of following formula
Wherein
* represent and group L 1link position,
And
* represents and group L 2link position,
R 2Brepresent hydrogen, methyl or trifluoromethyl
And
R 2Crepresent hydrogen or methyl, described methyl can be replaced by hydroxycarbonyl group, methoxycarbonyl or aminocarboxyl,
L 2represent key or group-CH 2-
And
Ar 2represent phenyl, described phenyl is selected from following identical or different residue list or two replacements: fluorine, chlorine, methyl, trifluoromethyl, methoxyl group and trifluoromethoxy.
Independent of the combination of the residue provided separately, the definition of the residue provided in detail in each combination or preferably combination of residue is also substituted arbitrarily by the definition of the residue of other combination.The combination of 2 or more above-mentioned preferable range is the most particularly preferred.
In addition, theme of the present invention is the method for the preparation of formula (I) compound according to the present invention, it is characterized in that,
In the presence of a base, 5-aryl-1,2, the 4-triazolone derivative of formula (II) is made
Wherein Ar 1and R 1there is the implication provided above,
[A] and formula (III) compound are obtained by reacting the compound of formula (I)
Wherein Ar 2, L 1, L 2, Q, R 2with n, there is the implication provided above
And
X 1represent leavings group such as chlorine, bromine, iodine, methanesulfonates or tosylate,
Or
[B] in a replacement scheme, the L in formula (I) 2represent key and group Ar 2when being connected with the carbon atom of ring Q,
React with formula (IV) compound
Wherein L 1, Q, R 2with n, there is the implication provided above,
X 1represent leavings group such as chlorine, bromine, iodine, methanesulfonates or tosylate
And
X 2represent the leavings group be connected with the carbon atom of ring Q, such as chlorine, bromine, iodine, methanesulfonates or trifluoromethane sulfonic acid ester,
Obtain the intermediate of formula (V)
Wherein Ar 1, L 1, Q, R 1, R 2, X 2with n, there is the implication provided above,
Then, under having suitable transition-metal catalyst to exist, itself and the coupling of formula (VI) compound is made,
Wherein Ar 2there is the implication provided above
And
M represents the group of following formula :-B (OR 4) 2,-MgHal ,-ZnHal or-Sn (R 5) 3, wherein
Hal represents halogen, especially chlorine, bromine or iodine,
R 4represent hydrogen or (C 1-C 4)-alkyl, or two residue R 4be connected with each other and common formation-(CH 2) 2-,-C (CH 3) 2-C (CH 3) 2-,-(CH 2) 3-or-CH 2-C (CH 3) 2-CH 2-bridge
And
R 5represent (C 1-C 4)-alkyl,
Obtain the compound of formula (I-A)
Wherein Ar 1, Ar 2, L 1, Q, R 1, R 2with n, there is the implication provided above,
Or
[C] in a replacement scheme, the L in formula (I) 2represent group-(CR as defined above 3Ar 3B) p-, and when being connected with the nitrogen-atoms of ring Q,
React with formula (VII) compound
Wherein L 1, R 2with n, there is the implication provided above,
Q' represents as above at the undefined 5 yuan of heteroaryl rings of Q, and it contains the trivalent ring-nitrogen-atoms be connected with the hydrogen atom of instruction,
And
X 1represent leavings group such as chlorine, bromine, iodine, methanesulfonates or tosylate,
Obtain the intermediate of formula (VIII)
Wherein Ar 1, L 1, Q', R 1, R 2with n, there is the implication provided above,
Then in the presence of a base, with formula (IX) compound by its N-alkylation
Wherein Ar 2there is the implication provided above,
L 2Arepresent group-(CR as defined above 3Ar 3B) p-,
And
X 3represent leavings group such as chlorine, bromine, iodine, methanesulfonates or tosylate,
Obtain formula (I-B) compound
Wherein Ar 1, Ar 2, L 1, L 2A, Q', R 1, R 2with n, there is the implication provided above,
And optionally the compound separation of the formula so obtained (I), (I-A) or (I-B) is become their enantiomer and/or diastereomer, and/or change into the solvate of their solvate, salt and/or described salt with suitable (i) solvent and/or (ii) alkali or acid.
For method steps (II)+(III) → (I), (II)+(IV) → (V), (II) inert solvent of+(VII) → (VIII) and (VIII)+(IX) → (I-B) is such as halohydrocarbon such as methylene dichloride, trichloromethane, tetracol phenixin, trieline or chlorobenzene, ether is ether such as, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), 1, 4-diox, 1, 2-glycol dimethyl ether or two-(2-methoxy ethyl) ether, hydrocarbon is benzene such as, toluene, dimethylbenzene, pentane, hexane, hexanaphthene or petroleum fractions, or dipolar aprotic solvent such as acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, n,N-dimethyl formamide (DMF), n,N-N,N-DIMETHYLACETAMIDE (DMA), dimethyl sulfoxide (DMSO) (DMSO), n, N'-dimethyl propylene thiazolinyl urea (DMPU), n-methyl-2-pyrrolidone (NMP) or pyridine.The mixture of described solvent can be used equally.Preferred use tetrahydrofuran (THF), acetonitrile, acetone or dimethyl formamide.
The alkali being applicable to method steps (II)+(III) → (I), (II)+(IV) → (V), (II)+(VII) → (VIII) and (VIII)+(IX) → (I-B) is conventional inorganic or organic bases.Preferably include: alkali metal hydroxide is lithium hydroxide, sodium hydroxide or potassium hydroxide such as this reason, basic metal-or alkaline earth metal carbonate be Quilonum Retard, sodium carbonate, salt of wormwood, calcium carbonate or cesium carbonate such as, alkali metal alcoholates such as sodium methylate or potassium methylate, sodium ethylate or potassium ethylate or sodium tert-butoxide or potassium tert.-butoxide, alkalimetal hydride such as sodium hydride or potassium hydride KH, aminocompound is sodium amide, two (trimethyl silyl) Lithamide or two (trimethyl silyl) potassium amide or lithium diisopropylamine such as, or organic amine such as triethylamine, n-methylmorpholine, n-methyl piperidine, n,N-diisopropylethylamine, pyridine, 1,5-diazabicyclo [4.3.0]-5-in ninth of the ten Heavenly Stems alkene (DBN), 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene (DBU) or Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane (DABCO ?).Preferred use salt of wormwood or cesium carbonate or sodium hydride.
Here, based on the compound meter of the formula of 1 mole (II) or (VIII), with the amount of 1-5 mol, preferably with the amount of 1-2.5 mol, described alkali is used.These method stepss can optionally advantageously carry out under the condition adding alkylation catalyst, and described catalyzer is such as lithiumbromide, sodium iodide, tetra-n-butyl ammonium bromide or benzyltriethylammoinium chloride.Described reaction usually-20 DEG C to+150 DEG C, preferably carry out the temperature range of 0 DEG C to+80 DEG C.Described reaction can at ambient pressure, the pressure raised or under a reduced pressure (such as 0.5-5 bar) carry out; Generally speaking, described reaction carries out at ambient pressure.
The inert solvent being applicable to method steps (V)+(VI) → (I-A) is, such as, aromatic hydrocarbon is benzene, toluene or dimethylbenzene such as, ether is ether, diisopropyl ether, methyl tertiary butyl ether, 1 such as, 2-glycol dimethyl ether, two-(2-methoxy ethyl) ether, tetrahydrofuran (THF) or 1,4-diox, or dipolar aprotic solvent such as acetonitrile, n,N-dimethyl formamide (DMF), n,N-N,N-DIMETHYLACETAMIDE (DMA), dimethyl sulfoxide (DMSO) (DMSO), n, N'-dimethyl propylene thiazolinyl urea (DMPU), n-methyl-2-pyrrolidone (NMP) or pyridine.Equally also can use the mixture of described solvent.Preferred use toluene, tetrahydrofuran (THF), Isosorbide-5-Nitrae-diox or dimethyl formamide.
Linked reaction (V)+(VI) → (I-A) carries out by means of transition-metal catalyst usually.For this reason suitable catalyzer is, copper catalyst is cupric iodide (I) such as, especially palladium catalyst such as activated carbon-carried palladium, acid chloride (II), two (triphenylphosphinyl) Palladous chloride (II), two (acetonitrile) Palladous chloride (II), [1, two (diphenylphosphino) ferrocene of 1'-] Palladous chloride (II), two (dibenzalacetone) palladium (0), three (dibenzalacetone) two palladium (0) or four (triphenylphosphinyl) palladium (0), other optional and following phosphine part is combined: such as tri-butyl phosphine, 2-dicyclohexyl phosphino--2'-( n,N-dimethylamino) biphenyl, dicyclohexyl [2', 4', 6'-tri-(1-methylethyl) biphenyl-2-base] phosphine (XPHOS) or 4, two (diphenylphosphino)-9 of 5-, 9-dimethyl xanthene (Xantphos) [see, such as, the people such as J. Hassan chem. Rev. 102, 1359-1469 (2002), V. Farina, V. Krishnamurthy and W.J. Scott, is shown in: the Stille Reaction, Wiley, New York, 1998].
With coupling [M=B (OR of aryl-boric acid ester 4) 2; " Suzuki coupling "] usually carry out when adding mineral alkali.For this reason it is suitable that, especially alkaline carbonate, alkali metal hydrocarbonate, alkali metal phosphate, alkali metal hydrogen phosphate, alkali metal acetate or alkaline metal fluoride cpd, such as sodium carbonate, salt of wormwood, sodium bicarbonate, saleratus, potassiumphosphate, Sodium phosphate dibasic, dipotassium hydrogen phosphate, sodium-acetate, potassium acetate, Potassium monofluoride and cesium fluoride.Such alkali also can use with the form of their aqueous solution.Preferred use sodium carbonate or salt of wormwood or potassiumphosphate.
Method steps (V)+(VI) → (I-A) usually+20 DEG C to+200 DEG C, preferably+60 DEG C to+150 DEG C temperature range, carry out at ambient pressure.But, also can carry out at the pressure reduced or under the pressure raised (such as 0.5-5 bar).Can optionally advantageously react under microwave exposure.
In a special scheme of aforesaid method [A], also can optionally prepare as follows thus according to formula of the present invention (I) compound:
Alternative compounds (II), first makes temporarily protected 1,2, the 4-triazolone derivative of formula (X)
Wherein Ar 1there is the implication provided above
And
PG represents suitable protecting group, such as allyl group or to methoxy-benzyl,
React with formula (III) compound;
The product of the formula (XI) obtained thus
Wherein Ar 1, Ar 2, L 1, L 2, PG, Q, R 2with n, there is the implication provided above,
After protecting group is dissociated, obtain formula (XII) compound
Wherein Ar 1, Ar 2, L 1, L 2, Q, R 2with n, there is the implication provided above,
It is then that induced by alkali with reaction that is formula (XIII) compound,
Wherein R 1there is the implication provided above
And
X 4represent leavings group such as chlorine, bromine, iodine, methanesulfonates or tosylate,
Change into corresponding formula (I) compound.
Similar conversion PG → R 1equally also optionally can occur in the process of aforesaid method scheme [B] and [C], in each case, carry out from protected aryltriazolin (ethi) ones (X).
Formula (XI) compound of some such PG protections has significant vasopressin antagonistic effect equally, and is therefore also included in the scope of the present invention's (i.e. formula (I) compound).
The introducing of protecting group PG and dissociating, the ordinary method known according to document is carried out [see, such as, T.W. Greene and P.G.M. Wuts, protective Groups in Organic Synthesis, Wiley, New York, 1999].Thus, preferably under the existence of tetrakis triphenylphosphine palladium (0) catalyzer and amine alkali (such as triethylamine), by means of formic acid removing allyl group.Preferably by means of strong acid (such as, trifluoracetic acid), or with method for oxidation, such as, by carrying out dissociating to methoxy-benzyl protecting group with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or cerium ammonium nitrate (IV) process.
Reaction (XII)+(XIII) → (I) carrying out subsequently similarly with above-mentioned method steps (II)+(III) → (I).Here, preferred inert solvent is acetone, acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), toluene, tetrahydrofuran (THF), glycol dimethyl ether and composition thereof.Preferably be used as alkali, sodium hydride or salt of wormwood or cesium carbonate.Described reaction usually at ambient pressure 0 DEG C to+150 DEG C, preferably carry out the temperature range of+20 DEG C to+80 DEG C.
Can from the carbohydrazide of formula (XIV), by reacting with the isocyanic ester of formula (XV) or the nitrophenylcarbamate of formula (XVI), and carry out the cyclisation of the hydrazine carboxamide intermediate (XVII) of alkali induction subsequently, 1 of preparation formula (II), 2,4-triazolone derivative (see chart 1):
chart 1
In a similar fashion, also can obtain 1,2,4-triazolone derivative of temporary transient protected formula (X), especially wherein PG represents allyl group or to those of methoxy-benzyl.
Wherein L 1expression-CH 2-, and L 2represent that formula (III) compound of key such as can be similar to aforesaid method [B] and prepare (chart 2) by the free radical of the coupling of transition metal-catalyzed formula (VI) compound and formula (XVIII) compound and intermediate (XIX) is subsequently halogenated:
chart 2
In a scheme of the method, carry out coupling with the ester derivative of formula (XX); Reduce the primary alconol of an accepted way of doing sth (XXII) subsequently, and according to document, hydroxy functional group changed into leavings group routinely, obtain the compound (chart 3) of the correspondence of formula (III-B):
Chart 3
In a similar fashion, formula (III) compound (wherein L 1expression-CH 2-, and L 2represent the group-(CR be connected with the nitrogen-atoms of ring Q 3Ar 3B) p-) can be prepared by the corresponding carboxylicesters of formula (XXIV), these parts can be similar to aforesaid method [C] and obtain (see chart 4):
chart 4
Ring Q according to the present invention represents that formula (I) compound of 5 yuan of heteroaryl rings also can optionally be prepared by complete synthesis relevant heteroaromatic system according to the method that document is known.Reaction chart 5-10 below can exemplarily explain such operational path:
chart 5 q=imidazolyl or thiazolyl
chart 6 q=1,2,3-triazoles base
chart 7 q=1,2,3-triazoles base (positional isomers)
chart 8 q=1,2,4-triazolyl
chart 9 q=1,2,4-evil di azoly
chart 10 q=1,2,4-evil di azoly (positional isomers)
If properly, also can pass through to transform each residue and substituent functional group, especially at R 1, R 2, Ar 1and Ar 2under list those prepare compound according to other formula (I) of the present invention, wherein from other formula (I) compound obtained according to the method described above.These transform the method be familiar with according to conventional those skilled in the art and carry out; and comprise such as following reaction: nucleophilic or the substitution reaction of parent's electricity, the linked reaction (such as Suzuki-or Heck-reaction) of transition metal mediation, oxidation, reduction, hydrogenation, alkylation, acidylate, amination, hydroxylation, etherificate, esterification, ether-splitting solution and ether be hydrolyzed, formation nitrile, carboxamide, sulphonamide, carbamate and urea and introducing and the interim protecting group [also see the preparation of the working Examples described in detail in experimental section below] of removing.
The alkylation of 5-aryl-1,2, the 4-triazole-3-ketone of the formula (II) of being induced by alkali and the halogenated acetic acid ester of formula (XLVII), can the intermediate of preparation formula (XXXVI) in a straightforward manner; By Ester hydrolysis subsequently, the corresponding carboxylic acid (see chart 11) of formula (XXV) can be obtained:
chart 11
Or, also can by document [see, such as, M. Arnswald, W.P. Neumann, j. Org. Chem. 58(25), 7022-7028 (1993); E.P. Papadopoulos, j. Org. Chem. 41(6), 962-965 (1976)] known formula (XLIX) n-(alkoxy carbonyl) arylthio acid amides, by reacting with the diazanyl acetic ester of formula (XLVIII), and subsequently on the N-4 of triazolone (L) alkylation carry out the compound (chart 12) of preparation formula (XXXVI):
chart 12
According to accessibility, also just compound separation according to the present invention can be become corresponding enantiomer and/or diastereomer at such as each intermediate stage listed above, wherein then described intermediate, according to above-mentioned method steps, reacts further with the form be separated.The separation of such steric isomer can be carried out according to ordinary method well known by persons skilled in the art; Preferred use chromatographic process, especially in the HPLC chromatography that achirality or chirality are gone up mutually.
Formula (IV), (VI), (VII), (IX), (XIII), (XIV), (XV), (XVI), (XVIII), (XX), (XXIII), (XXVI), (XXXI), (XXXIV), (XXXVIII), (XXXIX), (XLIII), (XLV), (XLVII), (XLVIII) and the compound of (XLIX) be obtained commercially, or as be described in document those, or they can be prepared in a manner apparent to those skilled in the art to be similar to disclosed method in the literature.In experimental section in the part of raw materials and intermediate, also there are the many detailed operation for raw materials and data in literature.
Compound according to the present invention has valuable pharmacological property, and may be used for preventing and/or treating the state that the various diseases of human and animal and disease cause.
Compound according to the present invention is V1a-, V2-of effective as selective or dual V1a/V2-receptor antagonist, and it suppresses vassopressin active in vitro and in vivo.In addition, also work as the antagonist of relevant ocytocin receptor according to compound of the present invention.
Compound according to the present invention is particularly suitable for preventing and/or treating cardiovascular disorder.In this respect, can be exemplary and preferably mention as target indication: acute and chronic heart failure, Arterial Hypertention, coronary heart disease, stable form and unstable angina pectoris, myocardial ischemia, myocardial infarction, shock, arteriosclerosis, room and ventricular arrhythmia, temporary and ischemic seizure of disease, apoplexy, inflammatory cardiovascular disease, periphery and cardiovascular disease, peripheral circulatory disturbances, artery pulmonary hypertension, the spasm of coronary artery and peripheral arterial, thrombosis, thrombotic disease, oedema forms (such as pulmonary edema, cerebral edema, renal edema or oedema in heart failure relevant) and restenosis (as at thromboembolism treatment, percutaneous transluminal angio plasty (PTA), transluminal coronary angioplasty (PTCA), after heart transplantation and bypass are performed the operation).
Within the scope of the present invention, term heart failure also comprises more specifically or relevant disease form, such as right heart failure, left heart failure, overall exhaustion (Globalinsuffizienz), ischemic cardiomyopathy, dilated cardiomyopathy, congenital heart defects, heart valve defect, with the heart failure of heart valve defect, mitral stenosis, mitral incompetence, aortic stenosis, aortic incompetence, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonic insufficiency, compound heart valve defect, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetes are in heart failure, alcoholic cardiomyopathy, heart storage disease, diastolic heart failure and systole heart failure.
In addition, compound according to the present invention is suitable as diuretic(s) and is used for the treatment of oedema and electrolyte disturbance, especially when hypervolemic hyponatremia normal with Q volume of blood.
Also be applicable to prevent and/or treat POLYCYSTIC KIDNEY DISEASE (PCKD) and ADH hyposecretion syndrome (SIADH) according to compound of the present invention.
In addition, compound according to the present invention may be used for preventing and/or treating liver cirrhosis, ascites, diabetes and diabetic complication, such as neuropathy and ephrosis, acute and chronic renal failure and chronic renal insufficiency.
In addition, compound according to the present invention is applicable to prevent and/or treat CNS disorders (such as anxiety state and depression), glaucoma and cancer, especially lung tumor.
In addition, compound according to the present invention may be used for preventing and/or treating inflammatory diseases, asthma disease, chronic obstructive airway disease (COPD), pain status, prostatomegaly, incontinence, bladder inflammation, Bladder hyperactivity, adrenal gland diseases (such as pheochromocytoma and adrenal apoplexy), intestinal disease (such as Crohn disease and diarrhoea) or menoxenia (such as dysmenorrhoea) or endometriosis.
Because their activity profile, compound according to the present invention is particularly suitable for treating and/or preventing acute and chronic heart failure, hypervolemic and the normal hyponatremia of Q volume of blood, liver cirrhosis, ascites, oedema and ADH hyposecretion syndrome (SIADH).
Another theme of the present invention is, compound according to the present invention is used for the treatment of and/or preventing disease, especially above-mentioned disease purposes.
Another theme of the present invention is, compound according to the present invention is for the production of the purposes of medicine, and described medicine is used for the treatment of and/or preventing disease, especially above-mentioned disease.
Another theme of the present invention is, compound according to the present invention be used for the treatment of and/or preventing disease, especially above-mentioned disease method in purposes.
Another theme of the present invention is, uses at least one compound according to the present invention of significant quantity to treat and/or prevent the method for disease, especially above-mentioned disease.
Compound according to the present invention can be used alone, or can use with other active substance combination when needed.Another theme of the present invention is, containing at least one according to the medicine of compound of the present invention with one or more other active substances, it is particularly useful for treating and/or preventing above-mentioned disease.Can exemplarily and preferably mention following as the combination activity substance being applicable to this object:
● organic nitrate and NO donor, the NO of such as Sodium Nitroprusside, pannonit, isosorbide mononitrate, Dilatrate-SR, molsidomine or SIN-1 and suction;
● diuretic(s), especially loop diuretic(s) and thiazide diuretic and thiazine analogue diuretic(s);
● positivity variable force active compound is cardiac glycoside (digoxin), beta-adrenergic and dopaminergic agonist such as Racemic isoproterenol, suprarenin, norepinephrine, Dopamine HCL and dobutamine such as;
● suppress the compound of the degraded of cGMP (cGMP) and/or ring AMP (cAMP), the such as inhibitor of phosphodiesterase (PDE) 1,2,3,4 and/or 5, especially PDE 5 inhibitor, such as Virga, Vardenafil and Tadalafei and PDE 3 inhibitor such as amrinone and milrinone;
● natriuretic peptide is " Natriuretic factor, atrial " (ANP, Wy 47663), " B-type natriuretic peptide " or " brain natriuretic peptide " (BNP, Nesiritide), " C-type natriuretic peptide " (CNP) and urodilatin such as;
● calcium sensitizing agent, such as and preferably Simdax;
● do not rely on the guanylate cyclase activators of NO and protoheme, the compound of such as especially Cinaciguat and description in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;
But ● do not rely on the guanylate cyclase stimulant that NO depends on protoheme, the compound of such as especially Riociguat and description in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;
● the inhibitor of people's Neutrophil elastase (HNE), such as sivelestat or DX-890 (Reltran);
● suppress the compound of signal transduction cascade, such as tyrosine kinase inhibitor, especially Xarelto, imatinib, Gefitinib and Tarceva;
● affect the compound of the energy metabolism of heart, such as and preferably benefit holder certain Xi Er, dichloroacetate/ester, ranolazine or trimetazidine;
● there is the reagent of anti thrombotic action, such as and be preferably selected from thrombocyte aggregation inhibitor, anti-coagulant or cause (profibrinolytische) material of fibrinolytic;
● the active substance reduced blood pressure, such as and be preferably selected from calcium antagonist, Angiotensin AII antagonist, ACE inhibitor, vasopeptidase inhibitors, neutral endopeptidase inhibitor, endothelin antagonist, renin inhibitor, alpha-blocking agent, beta-blocker, mineralocorticoid receptor antagonists and Rho-kinase inhibitor; And/or
● change lipometabolic active substance, such as and be preferably selected from thryoid receptor agonist, cholesterol synthesis inhibitor (such as and preferably HMG-CoA-reductase enzyme or Squalene synthesis inhibitors, ACAT inhibitor, CETP inhibitor, MTP inhibitor, PPAR-α, PPAR-γ and/or PPAR-delta agonists), cholesterol absorption inhibitor, lipase inhibitor, the gallic acid sorbent material of polymerization, gallic acid cell reabsorption inhibitor and lipoprotein (a) antagonist.
In a preferred embodiment of the present invention, will according to compound of the present invention and diuretic(s) co-administered, described diuretic(s) such as and preferably Furosemide, bumetanide, torasemide, Hydrex, chlorothiazide, hydrochlorothiazide, Hydroflumethiazide, Methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, Diclofenamide, methazolamide, glycerine, Isosorbide, N.F,USP MANNITOL, guanamprazine or triamterene.
Be interpreted as while there is the pharmacy optimization of anti thrombotic action and refer to, be selected from thrombocyte aggregation inhibitor, anti-coagulant or cause the compound of fibrinolytic material.
In a preferred embodiment of the present invention, will according to compound of the present invention and thrombocyte aggregation inhibitor co-administered, described thrombocyte aggregation inhibitor such as and preferably acetylsalicylic acid, clopidogrel, ticlopidine or Dipyridamole.
In a preferred embodiment of the present invention, according to compound of the present invention and thrombin inhibitors co-administered, described thrombin inhibitors is such as and preferably ximelagatran, Melagatran, dabigatran, Bivalirudin or gram match.
In a preferred embodiment of the present invention, use according to compound of the present invention and GPIIb/IIIa antagonist combination, described GPIIb/IIIa antagonist such as and preferably Tirofiban or ReoPro.
In a preferred embodiment of the present invention, according to compound of the present invention and factor Xa inhibitor co-administered, described factor Xa inhibitor such as and preferably razaxaban, DU-176b, Ah's paisa class, otamixaban, Fei Deshaban, razaxaban, fondaparin, Ai Zhuo heparin, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.
In a preferred embodiment of the present invention, according to compound of the present invention and heparin or lower molecular weight (LMW) heparin derivatives co-administered.
In a preferred embodiment of the present invention, according to compound of the present invention and vitamin K antagon co-administered, described vitamin K antagon such as and preferably tonka bean camphor.
Blood pressure lowering agent is preferably interpreted as and refers to and be selected from following compound: calcium antagonist, Angiotensin AII antagonist, ACE inhibitor, vasopeptidase inhibitors, neutral endopeptidase inhibitor, endothelin peptide antagonist, renin inhibitor, alpha-blocking agent, beta-blocker, mineralocorticoid receptor antagonists, Rho-kinase inhibitor and diuretic(s).
In a preferred embodiment of the present invention, according to compound of the present invention and calcium antagonist co-administered, described calcium antagonist such as and preferably nifedipine, amlodipine, verapamil or diltiazem .
In a preferred embodiment of the present invention, use according to compound of the present invention and Angiotensin AII antagonist combination, described Angiotensin AII antagonist such as and preferably losartan, Candesartan, valsartan, telmisartan or Embusartan.
In a preferred embodiment of the present invention, according to compound of the present invention and ACE inhibitor co-administered, described ACE inhibitor such as and preferably enalapril, captopril, lisinopril, Ramipril, delapril, fosinopril, quinapril (Quinopril), perindopril or Trandopril.
In a preferred embodiment of the present invention, according to compound of the present invention and vasopeptidase inhibitors or neutral endopeptidase inhibitor (NEP) co-administered, described inhibitor such as and preferably omapatrilat or AVE-7688.
In a preferred embodiment of the present invention, use according to compound of the present invention and endothelin peptide antagonist combination, described antagonist such as and preferably bosentan, darusentan, ambrisentan or sitaxentan.
In a preferred embodiment of the present invention, according to compound of the present invention and renin inhibitor co-administered, described renin inhibitor such as and preferably aliskiren, SPP-600 or SPP-800.
In a preferred embodiment of the present invention, according to compound of the present invention and α-1 receptor-blocking agent co-administered, described α-1 receptor-blocking agent such as and preferably Prazosin.
In a preferred embodiment of the present invention, according to compound of the present invention and beta-blocker co-administered, described beta-blocker such as and preferably Proprasylyte, atenolol USP 23, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, Carazolol (Carazalol), sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, Trate, carvedilol, Adaprolol, Landiolol, nebivolol, epanolol or bucindolol.
In a preferred embodiment of the present invention, according to compound of the present invention and mineralocorticoid receptor antagonists co-administered, described mineralocorticoid receptor antagonists such as and preferably spironolactone, eplerenone, canrenone or potassium canrenoate.
In a preferred embodiment of the present invention, according to compound of the present invention and Rho-kinase inhibitor co-administered, described Rho-kinase inhibitor such as and preferably fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095 or BA-1049.
Metabolism of fat changes agent and is preferably interpreted as and refers to and be selected from following compound: the gallic acid sorbent material of CETP inhibitor, thryoid receptor agonist, cholesterol synthesis inhibitor (such as HMG-CoA reductase or Squalene synthesis inhibitors, ACAT inhibitor, MTP inhibitor, PPAR-α, PPAR-γ and/or PPAR-delta agonists), cholesterol absorption inhibitor, polymerization, gallic acid cell reabsorption inhibitor, lipase inhibitor and lipoprotein (a) antagonist.
In a preferred embodiment of the present invention, according to compound of the present invention and CETP inhibitor co-administered, described CETP inhibitor such as and preferably torcetrapib, reach bent of plug, Ansai bent (Anacetrapib), BAY 60-5521 or CETP-vaccine (CETi-1).
In a preferred embodiment of the present invention, according to compound of the present invention and thryoid receptor agonist co-administered, described thryoid receptor agonist such as and preferably D-thyroxine, 3,5,3'-trilute (T3), CGS 23425 or axitirome (CGS 26214).
In a preferred embodiment of the present invention, according to compound of the present invention with to be selected from the HMG-CoA reductase inhibitor of Statins co-administered, described HMG-CoA reductase inhibitor such as and preferably lovastatin, Simvastatin, Pravastatin, fluvastatin, atorvastatin, rochovastatin or pitavastatin.
In a preferred embodiment of the present invention, according to compound of the present invention and Squalene synthesis inhibitors co-administered, described Squalene synthesis inhibitors such as and preferably BMS-188494 or TAK-475.
In a preferred embodiment of the present invention, according to compound of the present invention and ACAT inhibitor co-administered, described ACAT inhibitor such as and preferably avasimibe, Melinamide, handkerchief for wheat cloth, Eflucimibe or SMP-797.
In a preferred embodiment of the present invention, according to compound of the present invention and MTP inhibitor co-administered, described MTP inhibitor such as and preferably implitapide, BMS-201038, R-103757 or JTT-130.
In a preferred embodiment of the present invention, according to compound of the present invention and PPAR-gamma agonist co-administered, described PPAR-gamma agonist such as and preferably pioglitazone or rosiglitazone.
In a preferred embodiment of the present invention, according to compound of the present invention and PPAR-delta agonists co-administered, described PPAR-delta agonists such as and preferably GW-501516 or BAY 68-5042.
In a preferred embodiment of the present invention, according to compound of the present invention and cholesterol absorption inhibitor co-administered, described cholesterol absorption inhibitor such as and preferably Ezetimibe, tiqueside or Pamaqueside.
In a preferred embodiment of the present invention, according to compound of the present invention and lipase inhibitor co-administered, described lipase inhibitor such as and preferably orlistat.
In a preferred embodiment of the present invention, compound according to the present invention is co-administered with the gallic acid sorbent material be polymerized, described sorbent material such as and preferably Colestyramine, colestipol, Colesolvam, Cholestagel or Colestimide.
In a preferred embodiment of the present invention, according to compound of the present invention and gallic acid cell reabsorption inhibitor co-administered, described gallic acid cell reabsorption inhibitor such as and preferably ASBT (=IBAT) inhibitor, such as AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.
In a preferred embodiment of the present invention, use according to compound of the present invention and lipoprotein (a) antagonist combination, described lipoprotein (a) antagonist such as and preferably Gemcabene calcium (CI-1027) or nicotinic acid.
Another theme of the present invention is such medicine and the purposes for aforementioned object thereof: described medicine contains at least one according to compound of the present invention, usually with one or more inertia, nontoxic, pharmaceutically suitable vehicle.
Can work capapie and/or partly according to compound of the present invention.For this purpose, they can be used in an appropriate manner, such as oral, parenteral, lung, nose, sublingual, tongue, through cheek, rectum, corium, transdermal, conjunctiva or the approach of ear, or as implant or support.
With regard to these route of administration, can use with suitable form of medication according to compound of the present invention.
With regard to oral administration, such form of medication is suitable: described form of medication works according to prior art, rapidly and/or restrictively to discharge according to compound of the present invention, its contain crystallized form and/or amorphization form and/or solubilized form according to compound of the present invention, such as tablet (without dressing or the tablet of dressing, such as there is gastric juice resistance or delayed dissolved or insoluble dressing, described Drug coating controls the release according to compound of the present invention), quickly disintegrated tablet or film/starch paper in the oral cavity, film/lyophilisate, capsule (such as hard or Gelseal), dragee, particle, pill, powder, emulsion, suspension, aerosol or solution.
By getting around absorption step (administration in such as intravenous, endarterial, intracardiac, intraspinal or lumbar vertebrae), or by comprising absorption (such as intramuscular, subcutaneous, intracutaneous, through skin or endoperitoneal administration), can administered parenterally be realized.The form of medication being applicable to administered parenterally comprises with the injection formulations of solution, suspension, emulsion, lyophilisate or sterilized powder form and infusion.
With regard to other route of administration, it is suitable that, such as suck medicine form (especially powder inhalator and atomizer), nasal drop ,-solution or-spray, for tongue, sublingual or through the tablet of cheek administration, film/starch charta or capsule, suppository, ear-or ophthalmic preparation, vaginal capsule agent, aqueous suspension (lotion, jolting mixture), lipophilic suspension, ointment, ointment, transdermal therapeutic system (such as plaster), milk sap, paste, foam, face powder, implant or support.
Preferred oral or administered parenterally, especially oral and intravenous administration.
Form of medication described in converting compounds according to the present invention can being become.This can in a way known, realizes by mixing mutually with inertia, nontoxic, pharmaceutically suitable vehicle.These vehicle especially comprise carrier substance (such as Microcrystalline Cellulose, lactose, N.F,USP MANNITOL), solvent (such as liquid macrogol), emulsifying agent and dispersion agent or wetting agent (such as sodium lauryl sulphate, polyoxy sorbitan oleate), tackiness agent (such as polyvinylpyrrolidone), synthesis with natural polymkeric substance (such as albumin), stablizer (such as antioxidant such as xitix), tinting material (such as mineral dye such as ferric oxide) and taste-and/or smell corrigent.
Generally speaking, advantageously verified, the amount of about 0.001-10 mg/kg, preferably about 0.01-1 mg/kg body weight of using when administered parenterally is for obtaining effective result.When oral administration, described dosage is about 0.01-100 mg/kg, preferably about 0.01-20 mg/kg, and the most particularly preferably 0.1-10 mg/kg body weight.
However, sometimes may need to depart from described amount, namely depend on that body weight, route of administration, individuality are to the response of active substance, the type of preparation and time or the interval of carrying out administration.Thus, in some cases, being less than aforementioned minimum may being enough to deals with, and in other cases, must be over the described upper limit.Using in more substantial situation, may it is appropriate that to be divided into by this tittle in one day repeatedly individually dosed.
The following examples describe the present invention.The invention is not restricted to described embodiment.
Except as otherwise noted, the percent data described in following experiment and embodiment is weight percent, and number is parts by weight.The solvent ratio of liquid/liquid solution, thinning ratio and concentration data are respectively based on volumeter.
A. embodiment
Abbreviation and initialism:
Ac ethanoyl
AIBN 2,2'-azo two-2-methyl propionitrile
Alk alkyl
Boc tert-butoxycarbonyl
Ex. embodiment
CI chemi-ionization (in MS)
DCI direct chemical ionization (in MS)
DME 1,2-glycol dimethyl ether
DMF n,N-dimethyl formamide
DMSO dimethyl sulfoxide (DMSO)
(in the productive rate) of d. Th. theory
EDC n'-(3-dimethylamino-propyl)- n-ethyl-carbodiimide hydrochloride
Ee enantiomeric excess
EE ethyl acetate
Eq. equivalent
ESI electrospray ionisation (in MS)
GC/MS gas chromatography combined with mass spectrometry
Ges. saturated
H hour
Hal halogen
HOBt 1-hydroxyl-1 h-benzotriazole hydrate
HPLC high pressure-, high performance liquid chromatography
Konz. dense
LC/MS liquid chromatography mass unified analysis method
LDA lithium diisopropylamine
LiHMDS hexamethyldisilazane lithium
Min minute
MS mass spectroscopy
OAc acetic ester/salt
MTBE methyl tertiary butyl ether
NMR nuclear magnetic resonance spectrometry
pcontraposition
Ph phenyl
PyBOP benzotriazole-1-base oxygen base three (pyrrolidyl) phosphorus hexafluorophosphate
Quant. quantitatively (productive rate)
Rac is racemic/racemoid
RT room temperature
R tretention time (in HPLC)
THF tetrahydrofuran (THF)
TMOF trimethyl orthoformate
UV ultraviolet spectroscopy
V/v bulk for bulk (solution).
LC/MS-, GC/MS-and HPLC method:
method 1 (LC/MS):
Instrument type MS:Micromass ZQ; Instrument type HPLC:Waters Alliance 2795; Post: Phenomenex Synergi 2.5 μm of AX-RP 100A Mercury 20 mm x 4 mm; The formic acid of elutriant A:1 L water+0.5 ml 50%, the formic acid of elutriant B:1 L acetonitrile+0.5 ml 50%; Gradient: 0.0 min 90% A → 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.01 min 90% A; Flow velocity: 2 ml/min; Thermostat container: 50 DEG C; Ultraviolet detection: 210 nm.
method 2 (LC/MS):
Instrument: with the Micromass Quattro Micro MS of HPLC Agilent Serie 1100; Post: Thermo Hypersil GOLD 3 μ 20 mm x 4 mm; The formic acid of elutriant A:1 L water+0.5 ml 50%, the formic acid of elutriant B:1 L acetonitrile+0.5 ml 50%; Gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.01 min 100% A (flow velocity 2.5 ml/min) → 5.00 min 100% A; Thermostat container: 50 DEG C; Flow velocity: 2 ml/min; Ultraviolet detection: 210 nm.
method 3 (LC/MS):
Instrument: with the Micromass QuattroPremier of Waters UPLC Acquity; Post: Thermo Hypersil GOLD 1.9 μ 50 mm x 1 mm; The formic acid of elutriant A:1 L water+0.5 ml 50%, the formic acid of elutriant B:1 L acetonitrile+0.5 ml 50%; Gradient: 0.0 min 90% A → 0.1 min 90% A → 1.5 min 10% A → 2.2 min 10% A; Flow velocity: 0.33 ml/min; Thermostat container: 50 DEG C; Ultraviolet detection: 210 nm.
method 4 (LC/MS):
Instrument: Waters Acquity SQD UPLC System; Post: Waters Acquity UPLC HSS T3 1.8 μ 50 mm x 1 mm; The formic acid of elutriant A:1 L water+0.25 ml 99%, the formic acid of elutriant B:1 L acetonitrile+0.25 ml 99%; Gradient: 0.0 min 90% A → 1.2 min 5% A → 2.0 min 5% A; Flow velocity: 0.40 ml/min; Thermostat container: 50 DEG C; Ultraviolet detection: 210-400 nm.
method 5 (LC/MS):
Instrument type MS:Micromass ZQ; Instrument type HPLC:HP 1100 Series; UV DAD; Post: Phenomenex Gemini 3 μ 30 mm x 3.00 mm; The formic acid of elutriant A:1 L water+0.5 ml 50%, the formic acid of elutriant B:1 L acetonitrile+0.5 ml 50%; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow velocity: 0.0 min 1 ml/min → 2.5 min/3.0 min/4.5 min 2 ml/min; Thermostat container: 50 DEG C; Ultraviolet detection: 210 nm.
Method 6 (LC/MS):
Instrument type MS:Waters ZQ; Instrument type HPLC:Agilent 1100 Series; UV DAD; Post: Thermo Hypersil GOLD 3 μ 20 mm x 4 mm; The formic acid of elutriant A:1 L water+0.5 ml 50%, the formic acid of elutriant B:1 L acetonitrile+0.5 ml 50%; Gradient: 0.0 min 100% A → 3.0 min 10% A → 4.0 min 10% A → 4.1 min 100% A (flow velocity 2.5 ml/min); Thermostat container: 55 DEG C; Flow velocity: 2 ml/min; Ultraviolet detection: 210 nm.
method 7 (LC/MS):
Instrument type MS:Micromass ZQ; Instrument type HPLC:Waters Alliance 2795; Post: Phenomenex Synergi 2 μ hydrogen-RP Mercury 20 mm x 4 mm; The formic acid of elutriant A:1 L water+0.5 ml 50%, the formic acid of elutriant B:1 L acetonitrile+0.5 ml 50%; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow velocity: 0.0 min 1 ml/min → 2.5 min/3.0 min/4.5 min 2 ml/min; Thermostat container: 50 DEG C; Ultraviolet detection: 210 nm.
method 8 (LC/MS):
Instrument: with the Micromass Platform LCZ of HPLC Agilent Serie 1100; Post: Thermo Hypersil GOLD 3 μ 20 mm x 4 mm; The formic acid of elutriant A:1 L water+0.5 ml 50%, the formic acid of elutriant B:1 L acetonitrile+0.5 ml 50%; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 5.5 min 10% A; Flow velocity: 0.8 ml/min; Thermostat container: 50 DEG C; Ultraviolet detection: 210 nm.
method 9 (LC/MS):
Instrument: with the Micromass Quattro LCZ of HPLC Agilent Serie 1100; Post: Phenomenex Onyx Monolithic C18,100 mm x 3 mm; The formic acid of elutriant A:1 L water+0.5 ml 50%, the formic acid of elutriant B:1 L acetonitrile+0.5 ml 50%; Gradient: 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; Flow velocity: 2 ml/min; Thermostat container: 40 DEG C; Ultraviolet detection: 208-400 nm.
method 10 (LC/MS):
Instrument type MS:Waters ZQ; Instrument type HPLC:Waters Alliance 2795; Post: Phenomenex Onyx Monolithic C18,100 mm x 3 mm; The formic acid of elutriant A:1 L water+0.5 ml 50%, the formic acid of elutriant B:1 L acetonitrile+0.5 ml 50%; Gradient: 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; Flow velocity: 2 ml/min; Thermostat container: 40 DEG C; Ultraviolet detection: 210 nm.
method 11 (chiral analysis type HPLC):
Stationary phase: Daicel Chiralcel OD-H; Post: 250 mm x 4 mm; Flow velocity: 1 ml/min; Temperature: RT; Ultraviolet detection: 230 nm; Elutriant:
Method 11a: isohexane/Virahol 50:50 (v/v);
Method 11b: isohexane/methanol/ethanol 70:15:15 (v/v/v);
Method 11c: isohexane/Virahol 75:25 (v/v).
method 12 (chiral preparative HPLC):
Stationary phase: Daicel Chiralpak AD-H, 5 μm; Post: 250 mm x 20 mm; Temperature: 40 DEG C; Ultraviolet detection: 220 nm; Elutriant: isohexane/Virahol 80:20 (v/v); Flow velocity: 15 ml/min.
method 13 (chiral analysis type HPLC):
Stationary phase: Daicel Chiralpak AD-H, 5 μm; Post: 250 mm x 4.6 mm; Temperature: 40 DEG C; Ultraviolet detection: 220 nm; Elutriant: isohexane/Virahol 80:20 (v/v); Flow velocity: 1.0 ml/min.
method 14 (chiral analysis type HPLC):
Stationary phase: Daicel Chiralpak AD-H, 5 μm; Post: 250 mm x 4.6 mm; Temperature: 30 DEG C; Ultraviolet detection: 220 nm; Elutriant: the trifluoracetic acid 75:24:1 (v/v/v) of isohexane/Virahol/20%; Flow velocity: 1.0 ml/min.
method 15 (preparation HPLC):
Instrument: Abimed Gilson Pump 305/306, Manometric Module 806; Post: Grom-Sil 120 ODS-4HE, 10 μm, 250 mm x 30 mm; Elutriant A: water, elutriant B: acetonitrile; Gradient: 0.0 min 30% B → 3 min 30% B → 30 min 95% B → 42 min 95% B → 42.01 min 10% B → 45 min 10% B; Flow velocity: 50 ml/min; Column temperature: RT; Ultraviolet detection: 210 nm.
method 16 (preparation HPLC):
Post: Kromasil 100 C18,5 μm, 250 mm x 20 mm; The trifluoracetic acid of elutriant A:0.2%, elutriant B: acetonitrile; Deng degree 55% A, 45% B; Flow velocity: 25 ml/min; Column temperature: 30 DEG C; Ultraviolet detection: 210 nm.
method 17 (chiral preparative HPLC):
Stationary phase: Daicel Chiralpak AD-H, 5 μm; Post: 250 mm x 20 mm; Temperature: 40 DEG C; Ultraviolet detection: 220 nm; Elutriant: isohexane/ethanol 80:20 (v/v); Flow velocity: 15 ml/min.
method 18 (chiral analysis type HPLC):
Stationary phase: Daicel Chiralpak AS-H, 5 μm; Post: 250 mm x 4.6 mm; Temperature: 40 DEG C; Ultraviolet detection: 220 nm; Elutriant: isohexane/ethanol 80:20 (v/v); Flow velocity: 1 ml/min.
method 19 (preparation HPLC):
Post: Grom-Sil 120 ODS-4HE, 10 μm, 250 mm x 30 mm; Elutriant A: water, elutriant B: acetonitrile; Gradient: 0.0 min 10% B → 3 min 10% B → 30 min 95% B → 42 min 95% B → 42.01 min 10% B → 45 min 10% B; Flow velocity: 50 ml/min; Column temperature: RT; Ultraviolet detection: 210 nm.
method 20 (GC/MS):
Instrument: Micromass GCT, GC 6890; Post: Restek RTX-35,15 m x 200 μm x 0.33 μm; Constant helium flow velocity: 0.88 ml/min; Thermostat container: 70 DEG C; Entrance: 250 DEG C; Gradient: 70 DEG C, 30 DEG C/min → 310 DEG C (maintaining 3 min).
Starting compound and intermediate:
Embodiment 1A
n-({ 2-[(4-chloro-phenyl-) carbonyl] diazanyl } carbonyl) glycine ethyl ester
At 50 DEG C, the suspension of 12.95 g (75.9 mmol) the 4-chlorobenzoyl hydrazine in the THF of 50 ml dryings is put into container in advance, and drips the solution of 10.0 g (77.5 mmol) 2-ethyl isocyanatoacetate in the THF of 100 ml dryings.Initial formation solution, then separates out precipitation.After adding end, described mixture is continued stirring 2 h, then in room temperature hold over night at 50 DEG C.By filtering to isolate crystal, use a small amount of washed with diethylether, and dry under a high vacuum.Obtain 21.43 g (89% of theoretical value) title compound.
LC/MS [method 1]: R t=1.13 min; M/z=300 (M+H) +
1H-NMR (DMSO-d 6, 400 MHz): δ= 1.19 (t, 3H), 3.77 (d, 2H), 4.09 (q, 2H), 6.88 (br. s, 1H), 7.57 (d, 2H), 7.91 (d, 2H), 8.21 (s, 1H), 10.29 (s, 1H)。
Embodiment 2A
[3-(4-chloro-phenyl-)-5-oxo-1,5-dihydro-4 h-1,2,4-triazole-4-yl] acetic acid
91 ml 3 N aqueous sodium hydroxide solutions are added 21.43 g (67.9 mmol) derive from the compound of embodiment 1A, and heated overnight under reflux.After being cooled to room temperature, by adding the hydrochloric acid of about 20% lentamente, this mixture is adjusted to pH 1.By filtering to isolate the solid of precipitation, wash with water, and dry in a vacuum at 60 DEG C.Obtain 17.55 g (90% of theoretical value) title compound, purity is about 88%.
LC/MS [method 1]: R t=0.94 min; M/z=254 (M+H) +
1H-NMR (DMSO-d 6, 400 MHz): δ= 4.45 (s, 2H), 7.65-7.56 (m, 4H), 12.09 (s, 1H), 13.25 (br. s, 1H)。
Embodiment 3A
5-(4-chloro-phenyl-)-4-(the fluoro-2-oxopropyl of 3,3,3-tri-)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone ( ketone form) or 5-(4-chloro-phenyl-)-4-(fluoro-2, the 2-dihydroxypropyls of 3,3,3-tri-)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone ( hydrate forms)
Under argon gas, 5.0 g (16.36 mmol) are derived from the compound dissolution of embodiment 2A in 200 ml pyridines, and add 17.18 g (81.8 mmol) trifluoroacetic anhydride.In adition process, temperature is increased to about 35 DEG C.After 30 min, remove pyridine on the rotary evaporator, and 1.5 liter of 0.5 N hydrochloric acid is added in resistates.This mixture is heated to 70 DEG C, then filtered while hot.With a small amount of water washing solid.All filtrate is extracted with ethyl acetate 3 times.Successively by the organic phase that the washing of water, saturated sodium bicarbonate solution and saturated nacl aqueous solution merges, through dried over sodium sulfate, and on the rotary evaporator except desolventizing.Dried residue under a high vacuum.Obtain the title compound of 3.56 g (68% of theoretical value) hydrate forms.
LC/MS [method 1]: R t=1.51 min; M/z=306 (M+H) +with 324 (M+H) +(ketone or hydrate forms)
1H-NMR (DMSO-d 6, 400 MHz): δ= 3.98 (s, 2H), 7.61 (d, 2H), 7.68 (br. s, 2H), 7.72 (d, 2H), 12.44 (s, 1H)。
Embodiment 4A
5-(4-chloro-phenyl-)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
3.56 g (11.0 mmol) are derived from the compound dissolution of embodiment 3A in 100 ml methyl alcohol, and add 3.75 g (99.5 mmol) sodium borohydride under ice-cooling.After 1.5 h, add 200 ml 1 M hydrochloric acid lentamente.Remove methyl alcohol on the rotary evaporator, with 500 ml water dilution resistatess, and be extracted with ethyl acetate 3 times.With saturated sodium bicarbonate solution with subsequently by the organic phase that saturated nacl aqueous solution washing merges, through dried over sodium sulfate, and on the rotary evaporator except desolventizing.Dried residue under a high vacuum.Obtain 3.04 g (90% of theoretical value) title compound.
LC/MS [method 2]: R t=1.80 min; M/z=308 (M+H) +
1H-NMR (DMSO-d 6, 400 MHz): δ= 3.77 (dd, 1H), 3.92 (dd, 1H), 4.34-4.23 (m, 1H), 6.85 (d, 1H), 7.62 (d, 2H), 7.75 (d, 2H), 12.11 (s, 1H)。
Embodiment 5A
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
1.08 g (3.3 mmol) are derived from the compound dissolution of embodiment 3A in 11 ml n,Nin-N,N-DIMETHYLACETAMIDE.This solution is removed atmospheric oxygen by means of vacuum, and saturated with argon.Under argon, by 21 mg (0.033 mmol) ( n-[(1 s, 2 s)-( +) amino-1, the 2-diphenyl-ethyl of-2-] (4-tosyl group) amido) (p-cymene) ruthenium chloride (II) [CAS registration number 192139-90-5] adds in this solution.Then add the mixture of 0.63 ml (16.6 mmol) formic acid and 0.27 ml (1.91 mmol) triethylamine, and isolated air at room temperature stirs 48 h.For carrying out aftertreatment, described mixture is added in 10 ml 0.1 N hydrochloric acid, and with the extraction into ethyl acetate 2 times of each 20 ml.By the organic phase that saturated sodium bicarbonate solution washing merges, through dried over sodium sulfate, filter, and concentrate in a vacuum.By chromatography at purified over silica gel crude product (elutriant: cyclohexane/ethyl acetate 3:1, then 1:1).Obtain 830 mg (81% of theoretical value) target compound.
Recording enantiomeric excess (ee) according to method 14 by chromatography is 96%: senantiomer R t=5.73 min, renantiomer R t=6.82 min.
Embodiment 6A
{ 3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl acetate ( racemoid)
3.04 g (9.9 mmol) are derived from the compound dissolution of embodiment 4A in 100 ml acetonitriles, and add the potassiumiodide of 1.07 g (9.9 mmol) methyl chloroacetate, 2.73 g (19.8 mmol) salt of wormwood and little spatula point.Described reaction mixture is heated 1 h under reflux, is then cooled to room temperature, and filter.Filtrate is removed volatile constituent on the rotary evaporator, and dried residue under a high vacuum.Obtain 3.70 g title compounds (89% of theoretical value), purity is about 90%.
LC/MS [method 3]: R t=1.10 min; M/z=380 (M+H) +
1H-NMR (DMSO-d 6, 400 MHz): δ= 3.70 (s, 3H), 3.84 (dd, 1H), 3.99 (dd, 1H), 4.16-4.35 (m, 1H), 4.72 (s, 2H), 6.91 (d, 1H), 7.64 (d, 2H), 7.78 (d, 2H)。
Pass through preparation HPLC, by the racemic compound deriving from embodiment 6A chirality mutually on be separated into enantiomer [preparation of samples: be dissolved in by 3.6 g racemoids in 54 ml ethyl acetate/isohexanes (1:1 v/v), be divided into 3 parts and be separated by post; Post: based on selective agent poly-( n-methacryloyl-ILE-3-amyl group acid amides) chiral silica gel phase, 430 mm x 40 mm; Elutriant: notch cuttype gradient isohexane/ethyl acetate 1:1 → ethyl acetate → isohexane/ethyl acetate 1:1; Flow velocity: 50 ml/ min; Temperature: 24 DEG C; Ultraviolet detection: 260 nm].Obtain the 1.6 g first enantiomer 1 (embodiment 7A) of wash-out and the enantiomer 2 (embodiment 8A) of the more late wash-out of 1.6 g by this way:
Embodiment 7A
{ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl acetate ( enantiomer 1)
By the enantiomer of the racemoid first wash-out of embodiment 6A.
R t=3.21 min [post: based on selective agent poly-( n-methacryloyl-ILE-3-amyl group acid amides) chiral silica gel phase, 250 mm x 4.6 mm; Elutriant: isohexane/ethyl acetate 1:1; Flow velocity: 1 ml/min; Ultraviolet detection: 260 nm].
Embodiment 8A
{ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 r)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl acetate ( enantiomer 2)
By the enantiomer of wash-out after the racemoid of embodiment 6A.
R t=4.48 min [post: based on selective agent poly-( n-methacryloyl-ILE-3-amyl group acid amides) chiral silica gel phase, 250 mm x 4.6 mm; Elutriant: isohexane/ethyl acetate 1:1; Flow velocity: 1 ml/min; Ultraviolet detection: 260 nm].
Embodiment 9A
{ 3-(4-chloro-phenyl-)-5-oxo-4-[(1 e)-3,3,3-trifluoropropyl-1-alkene-1-bases]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl acetate
At room temperature, 5.0 g (13.12 mmol) are derived from compound and 1.93 g (15.8 mmol) 4-of embodiment 8A n,N-Dimethylamino pyridine puts into 70 ml pyridines together, and gradation adds 5.54 ml (32.92 mmol) Trifluoromethanesulfonic anhydride, and stirs 18 h.In order to carry out aftertreatment, adding 5 ml 1 N hydrochloric acid, and removing pyridine on the rotary evaporator.Resistates is dissolved in 50 ml ethyl acetate, and with 25 ml water washings.The aqueous phase ethyl acetate of each 25 ml is returned extraction 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography at purified over silica gel crude product (elutriant: cyclohexane/ethyl acetate 10:1, then 4:1).Obtain 3.50 g (73% of theoretical value) title compound.
LC/MS [method 4]: R t=1.14 min; M/z=362 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 7.68 (s, 4H), 7.18 (d, 1H), 6.85 (dd, 1H), 4.78 (s, 2H), 3.72 (s, 3H)。
Embodiment 10A
[3-(4-chloro-phenyl-)-5-oxo-4-(3,3,3-trifluoro propyl)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl acetate
1.3 g (3.59 mmol) are derived from the compound of embodiment 9A and 150 mg carbon to carry platinum (5%) and be dissolved in 150 ml methyl alcohol, and hydrogenation 18 h at ambient pressure.In order to carry out aftertreatment, leach catalyzer by diatomite, and concentrated filtrate on the rotary evaporator.Under a high vacuum after dried residue, obtain 1.26 g (89% of theoretical value) title compound, purity is 92%.
LC/MS [method 4]: R t=1.00 min; M/z=364 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 2.55-2.68 (m, 2H), 3.69 (s, 3H), 4.01 (t, 2H), 4.70 (s, 2H), 7.61-7.72 (m, 4H)。
Embodiment 11A
2-[(4-chloro-phenyl-) carbonyl]- n-(the third-2-alkene-1-base) hydrazine carboxylic acid amides
At 50 DEG C, 5.00 g (29.3 mmol) 4-chlorobenzoyl hydrazine is suspended in the THF of 150 ml dryings.Then 2.63 ml (29.9 mmol) allyl isocyanate be dissolved in the THF of 110 ml dryings is dripped.At first, all material dissolutions, then separate out trickle throw out.Described mixture is stirred 2 h at 50 DEG C.After being cooled to room temperature, add ether.Suction filtration colorless solid, with washed with diethylether, and dry under a high vacuum.Obtain 7.42 g (100% of theoretical value) target compound.
LC/MS [method 5]: R t=1.51 min; MS [ESIpos]: m/z=254 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.60-3.70 (m, 2H), 5.01 (dd, 1H), 5.14 (dd, 1H), 5.72-5.86 (m, 1H), 6.70 (s, 1H), 7.56 (d, 2H), 7.85-7.95 (m, 3H), 10.21 (s, 1H)。
Embodiment 12A
5-(4-chloro-phenyl-)-4-(the third-2-alkene-1-base)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
26.8 g (106 mmol) are derived from the 2-[(4-chloro-phenyl-) carbonyl] of embodiment 11A- n-(the third-2-alkene-1-base) hydrazine carboxylic acid amides is suspended in 210 ml 3 M aqueous sodium hydroxide solutions, and heats 20 h under reflux.After cooling, use half concentrated hydrochloric acid, pH is adjusted to 10.The colorless solid of suction filtration precipitation, is washed with water to neutrality, then stirs in methyl alcohol.By filtering, remove the insoluble component in described mixture, on the rotary evaporator vapourisation under reduced pressure concentrated filtrate, and dried residue under a high vacuum.Obtaining 21.5 g (86.4% of theoretical value) title compound like this, is colorless solid.
LC/MS [method 5]: R t=1.79 min; MS [ESIpos]: m/z=236 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 4.30-4.35 (m, 2H), 4.91 (dd, 1H), 5.11 (dd, 1H), 5.76-5.90 (m, 1H), 7.58 (d, 2H), 7.65 (d, 2H), 12.05 (s, 1H)。
Embodiment 13A
5-(4-chloro-phenyl-)-2-(the third-2-alkynes-1-base)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
300 mg (0.98 mmol) are derived from the compound dissolution of embodiment 4A in 10 ml acetonitriles, and add the bromo-1-propine of 122 mg (1.02 mmol) 3-and 270 mg (1.95 mmol) salt of wormwood.By described mixture reflux 1 h.In order to carry out aftertreatment, described reaction mixture is cooled to room temperature, and adds about 10 ml water.With mixture described in each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 166 mg (49% of theoretical value) target compound.
LC/MS [method 4]: R t=0.97 min; M/z=346 (M+H) +
1H-NMR (CDCl 3, 400 MHz): δ= 2.38 (t, 1H), 3.94-4.09 (m, 1H), 4.43-4.54 (m, 1H), 4.68 (d, 2H), 4.73-4.78 (m, 1H), 7.50 (d, 2H), 7.57 (d, 2H)。
Embodiment 14A
5-(4-chloro-phenyl-)-2-(the third-2-alkynes-1-base)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
1110 mg (3.61 mmol) are derived from the compound dissolution of embodiment 5A in 30 ml acetonitriles, and add the bromo-1-propine of 451 mg (3.79 mmol) 3-and 2.35 g (7.22 mmol) cesium carbonate.Described mixture is heated 1 h under reflux.In order to carry out aftertreatment, described reaction mixture is cooled to room temperature, and adds about 30 ml water.With mixture described in the extraction into ethyl acetate of each 30 ml 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography at purified over silica gel crude product (elutriant: cyclohexane/ethyl acetate 10:1, then 3:1).Obtain 203 mg (16% of theoretical value) title compound.
LC/MS [method 3]: R t=1.11 min; M/z=346 (M+H) +
1H-NMR (CDCl 3, 400 MHz): δ= 2.38 (t, 1H), 3.94-4.09 (m, 1H), 4.43-4.54 (m, 1H), 4.68 (d, 2H), 4.73-4.78 (m, 1H), 7.50 (d, 2H), 7.57 (d, 2H)。
Embodiment 15A
3-{ [3-(4-chloro-phenyl-)-1-(2-methoxyl group-2-oxoethyl)-5-oxo-1,5-dihydro-4 h-1,2,4-triazole-4-yl] methyl } methyl benzoate
By 200 mg (0.75 mmol) [3-(4-chloro-phenyl-)-5-oxo-4,5-dihydro-1 h-1,2,4-triazol-1-yl] methyl acetate [preparing according to WO 2007/134862 embodiment 222A] is suspended in 7.5 ml acetone, add 365 mg (1.12 mmol) cesium carbonate and 223 mg (0.97 mmol) 3-bromomethyl-benzoic acid methyl ester, and described mixture is heated 1 h to boiling.After cooling, filter described mixture by Extrelut, and use acetone rinsing.Concentrated filtrate in a vacuum, and by chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 4:1 → 1:1) Purification.Obtain target compound, be colourless foam (165 mg, 53% of theoretical value).
MS [DCI]: m/z = 433 (M+NH 4) +, 416 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.71 (s, 3H), 3.82 (s, 3H), 4.75 (s, 2H), 5.08 (s, 2H), 7.32 (d, 1H), 7.46 (t, 1H), 7.55 (s, 4H), 7.66 (s, 1H), 7.82 (d, 1H)。
Embodiment 16A
3-{ [3-(4-chloro-phenyl-)-1-(2-diazanyl-2-oxoethyl)-5-oxo-1,5-dihydro-4 h-1,2,4-triazole-4-yl] methyl } methyl benzoate
The compound that 172 mg (0.41 mmol) derive from embodiment 15A is suspended in 1 ml ethanol, and adds 40 μ l (0.83 mmol) hydrazine hydrate.Described mixture is heated 4 h under reflux, then leaves standstill 18 h in room temperature.Under reduced pressure concentration response thing on the rotary evaporator, and dried residue under a high vacuum.Obtaining 161 mg (94% of theoretical value) target compound like this, is colorless solid.
MS [DCI]: m/z = 433 (M+NH 4) +, 416 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.82 (s, 3H), 4.31 (d, 2H), 4.43 (s, 2H), 5.05 (s, 2H), 7.37 (d, 1H), 7.42-7.57 (m, 5H), 7.71 (s, 1H), 7.83 (d, 1H), 9.30 (t, 1H)。
Obtain following compound in a similar fashion:
Embodiment 21A
2-[3-(4-chloro-phenyl-)-4-cyclopropyl-5-oxo-4,5-dihydro-1 h-1,2,4-triazol-1-yl] acethydrazide
By 50 mg (0.17 mmol) [3-(4-chloro-phenyl-)-4-cyclopropyl-5-oxo-4,5-dihydro-1 h-1,2,4-triazol-1-yl] acetic acid [preparing according to WO 2007/134862 embodiment 88A] is dissolved in 0.4 ml methyl alcohol, and by 0.6 ml dilution with toluene, then 128 μ l (0.26 mmol) trimethyl silyl diazomethane solution (2 M in hexane) is dripped, until keep light yellow.Described reaction mass is stirred 1 h, is then concentrated into drying.Resistates is dissolved in 1 ml ethanol, adds 43 mg (0.85 mmol) hydrazine hydrate, and stir 2.5 h under reflux.After cooling, concentrated solution in a vacuum, and dried residue under a high vacuum.Obtain 54 mg (96% of theoretical value) title compound like this, purity is 93%, is colorless solid.
LC/MS [method 5]: R t=1.65 min; MS [ESIpos]: m/z=308 (M+H) +.
In a similar fashion, following 2 kinds of compounds are obtained:
Embodiment 24A
[3-(5-chlorothiophene-2-base)-4-(2-luorobenzyl)-5-oxo-4,5-dihydro-1 h-1,2,4-triazol-1-yl] acetonitrile
Under the oil bath temperature of 100 DEG C, by 250 mg (0.81 mmol) 5-(the chloro-2-thienyl of 5-)-4-(2-luorobenzyl)-2,4-dihydros-3 hthe mixture of-1,2,4-triazole-3-ketone [preparing according to WO 2007/134862 embodiment 154A], 67 μ l (0.97 mmol) bromoacetonitrile and 223 mg (1.61 mmol) salt of wormwood stirs 1 h in the DMF of 8 ml dryings.After cooling, by mixture described in diatomite filtration, under reduced pressure concentrated filtrate, and distribute resistates between MTBE and water.Successively by 10 ml water and 10 ml saturated nacl aqueous solutions washing organic phase, through dried over sodium sulfate, filter, and concentrate in a vacuum.By chromatography at residue purified on silica (elutriant: cyclohexane/ethyl acetate 4:1).Obtaining 258 mg (92% of theoretical value) target compound, is micro-yellow solid.
MS [DCI]: m/z = 366 (M+NH 4) +, 349 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 4.81 (s, 2H), 5.11 (s, 2H), 6.87 (d, 1H), 6.97 (s, 1H), 7.05-7.16 (m, 3H), 7.28-7.36 (m, 1H)。
Embodiment 25A
(1 z)-2-[3-(5-chlorothiophene-2-base)-4-(2-luorobenzyl)-5-oxo-4,5-dihydro-1 h-1,2,4-triazol-1-yl]- n'-hydroxyl acetamidine
The compound and 92 mg (1.32 mmol) oxammonium hydrochloride that 250 mg (0.66 mmol) are derived from embodiment 24A are suspended in 3.3 ml ethanol, and are heated to boiling.193 μ l (1.39 mmol) triethylamine is added in this hot solution, and continues heating 1 h under reflux.When reaction mass cools, crystallization colorless solid; This solid of suction strainer, and use a small amount of washing with alcohol.Obtaining 174 mg (69% of theoretical value) target compound like this, is colorless solid.Vapourisation under reduced pressure concentrated mother liquor on the rotary evaporator, and resistates is distributed between water and ethyl acetate.Successively by 10 ml water and 10 ml saturated nacl aqueous solutions washing organic phase, through dried over sodium sulfate, filter, and concentrate in a vacuum.Obtain other 69 mg (24% of theoretical value) target compound like this, purity is 87%, is micro-yellow solid.
MS [ESIpos]: m/z = 382 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 4.36 (s, 2H), 5.11 (s, 2H), 5.46 (s, 2H), 7.04-7.12 (m, 1H), 7.12-7.28 (m, 4H), 7.30-7.41 (m, 1H), 9.27 (s, 1H)。
Embodiment 26A
1-amino-3-[3-(trifluoromethyl) phenyl] acetone-hydrogenchloride
Under argon and under ice-cooling, 1.13 g (11.8 mmol) diformyl chlorseptol is added in batches in the solution of the chloro-3-of 2.67 g (11.2 mmol) 1-[3-(trifluoromethyl) phenyl] propane-2-ketone in 11 ml DMF.Described mixture is stirred 1 h, then in ambient temperature overnight in ice bath.Then mixture described in 25 ml diluted ethyl acetate is used, and successively with the 0.5 N hydrochloric acid of each 15 ml, water, saturated sodium bicarbonate solution washing, then wash 1 time with water.Organic phase, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.Prepurification (elutriant: methylene dichloride/alcohol 95: 5) dark oil residue on short silicagel column.So obtain 2.0 g dark brown solid.In the solution of the hydrogenchloride being dissolved in 25 ml 7 N in Virahol, and stir and spend the night.On the rotary evaporator under reduced pressure except desolventizing, resistates is dissolved in about 15 ml methyl alcohol.100 ml ether are stirred in this solution, and by solid that filtering separation precipitates.With about 10 ml diisopropyl ether filter cakes, and dry under a high vacuum.So obtaining 0.79 g (28% of theoretical value) target compound, is brown solid.
LC/MS [method 8]: R t=2.30 min; MS [ESIpos]: m/z=218 (M-HCl) +
1H-NMR (400 MHz, DMSO-d 6): δ= 4.00-4.11 (m, 4H), 7.49-7.70 (m, 4H), 8.17 (br. d, 1H)。
Embodiment 27A
2-[3-(4-chloro-phenyl-)-4-cyclopropyl-5-oxo-4,5-dihydro-1 h-1,2,4-triazol-1-yl]- n-{ 2-oxo-3-[3-(trifluoromethyl) phenyl] propyl group } ethanamide
391 mg (2.90 mmol) HOBt and 513 mg (2.67 mmol) EDC is added 654 mg (2.23 mmol) [3-(4-chloro-phenyl-)-4-cyclopropyl-5-oxo-4,5-dihydro-1 h-1,2,4-triazol-1-yl] acetic acid [preparing according to WO 2007/134862 embodiment 88A] and 650 mg (2.56 mmol) derive from embodiment 26A the solution of compound in the DMF of 4.4 ml dryings in.Then 465 μ l (2.67 mmol) are added n,N-diisopropylethylamine, and described reaction mass stirring is spent the night.In order to carry out aftertreatment, with 20 ml diluted ethyl acetate, and extract 2 times with each 15 ml water.Organic phase, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.The remaining resistates of recrystallization from acetonitrile.Obtaining 610 mg (56% of theoretical value) target compound, is very meticulous clear crystal.The secondary crystal of concentrated mother liquor, produces the target compound of other 84 mg (8% of theoretical value) micro-yellow crystals form.
MS [ESIpos]: m/z = 493 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.73-0.83 (m, 2H), 0.97-1.09 (m, 2H), 2.94-3.04 (m, 1H), 3.80 (s, 2H), 4.25 (d, 2H), 4.53 (s, 2H), 6.91-7.02 (m, 1H), 7.39 (d, 1H), 7.43-7.51 (m, 4H), 7.57 (d, 1H), 7.71 (d, 2H)。
Embodiment 28A
2-[(5-bromopyridine-3-base) methyl]-5-(4-chloro-phenyl-)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound and 953 mg (2.93 mmol) cesium carbonate that 300 mg (0.98 mmol) are derived from embodiment 4A are dissolved in 4 ml DMF, and add 261 mg (1.10 mmol) 3-bromo-5-(chloromethyl) pyridine-hydrogenchloride.First described mixture is stirred 20 h at 40 DEG C, then stir 24 h at 70 DEG C.In order to make to react completely, then add other 130 mg (0.55 mmol) 3-bromo-5-(chloromethyl) pyridine-hydrogenchloride and 450 mg (1.38 mmol) cesium carbonate, and described reaction mass is stirred other 20 h at 70 DEG C.After being cooled to room temperature, 10 ml water are added in this mixture, and with each 10 ml extraction into ethyl acetate 3 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By preparation HPLC [method 19], purification of crude product.Obtain 263 mg (56% of theoretical value) target compound.
LC/MS [method 4]: R t=1.07 min; MS [ESIpos]: m/z=477 and 479 (M+H) +.
Embodiment 29A
2-[(5-bromopyridine-3-base) methyl]-5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound and 543 mg (1.67 mmol) cesium carbonate that 171 mg (0.56 mmol) are derived from embodiment 5A are dissolved in 11 ml acetonitriles, and add 135 mg (0.56 mmol) 3-bromo-5-(chloromethyl) pyridine-hydrogenchloride.Described mixture is stirred 5 h at 65 DEG C.After being cooled to room temperature, 10 ml water are added described mixture, and with each 10 ml extraction into ethyl acetate 3 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By preparation HPLC [method 19], purification of crude product.Obtain 102 mg (38% of theoretical value) target compound.
LC/MS [method 4]: R t=1.05 min; MS [ESIpos]: m/z=477 and 479 (M+H) +.
Embodiment 30A
5-(4-chloro-phenyl-)-2-[(the chloro-2-thienyl of 5-) methyl]-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound and 107 mg (0.77 mmol) salt of wormwood that 119 mg (0.39 mmol) are derived from embodiment 5A are dissolved in 5 ml acetonitriles, and add 65 mg (0.39 mmol) 2-chloro-5-(chloromethyl) thiophene.Described mixture is stirred 2 h under reflux.After being cooled to room temperature, 10 ml water are added in this mixture, and with mixture described in each 10 ml extraction into ethyl acetate 3 times.By the organic phase that 10 ml saturated nacl aqueous solution washings merge, through dried over sodium sulfate, filter, and concentrate in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 10:1 → 8:1 → 5:1 → 1:1), purification of crude product.Obtain 114 mg (65% of theoretical value) target compound.
LC/MS [method 4]: R t=1.20 min; MS [ESIpos]: m/z=438 and 440 (M+H) +.
Embodiment 31A
5-(4-chloro-phenyl-)-2-[(the chloro-1,3-thiazoles of 2--5-base) methyl]-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound and 449 mg (3.25 mmol) salt of wormwood that 500 mg (1.63 mmol) are derived from embodiment 5A are dissolved in 4 ml acetonitriles, and add the 287 mg chloro-5-of (1.71 mmol) 2-(chloromethyl)-1,3-thiazoles.Described mixture is stirred 1.5 h at 80 DEG C.After being cooled to room temperature, 10 ml water are added in this mixture, and with mixture described in each 10 ml extraction into ethyl acetate 3 times.By the organic phase that 10 ml saturated nacl aqueous solution washings merge, through dried over sodium sulfate, filter, and concentrate in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 7:1, then 1:1), purification of crude product.Obtain 619 mg (87% of theoretical value) target compound.
LC/MS [method 3]: R t=1.24 min; MS [ESIpos]: m/z=439 and 441 (M+H) +.
Embodiment 32A
1-(2,6-dichloro benzyl)-1 h-imidazoles-5-ethyl formate
By 258 mg (1.84 mmol) 1 h-imidazoles-4-ethyl formate and 486 mg (2.03 mmol) 2,6-dichloro benzyl bromine are dissolved in 7 ml DMF together, and add 720 mg (2.21 mmol) cesium carbonate.Described mixture is stirred 16 h at 80 DEG C.After being cooled to room temperature, 10 ml water are added in this mixture, and with mixture described in each 10 ml extraction into ethyl acetate 2 times.The organic phase merged through dried over sodium sulfate, and removes desolventizing on the rotary evaporator.By chromatography [method 19] purification of crude product.Obtain 220 mg (40% of theoretical value) target compound.
LC/MS [method 3]: R t=1.03 min; MS [ESIpos]: m/z=299 and 301 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 1.37 (t, 3H), 4.34 (q, 2H), 5.44 (s, 2H), 7.27-7.33 (m, 1H), 7.37-7.43 (m, 2H), 7.68 (d, 2H)。
110 mg (20% of theoretical value) positional isomers 1-(2,6-dichloro benzyl)-1 is obtained in other fraction h-imidazoles-4-ethyl formate:
LC/MS [method 3]: R t=1.12 min; MS [ESIpos]: m/z=299 and 301 (M+H) +.
Embodiment 33A
1-(2,6-dichloro benzyl)-4-nitro-1 h-imidazoles-2-ethyl formate
By 1000 mg (5.4 mmol) 4-nitro-1 h-imidazoles-2-ethyl formate and 1426 mg (5.94 mmol) 2,6-dichloro benzyl bromine are dissolved in 37 ml DMF together, and add 2112 mg (6.48 mmol) cesium carbonate.Described mixture is stirred 4 h at 75 DEG C.After being cooled to room temperature, described mixture is added in 100 ml frozen water.Leach the product of precipitation, and wash with water.Dry brown solid under a high vacuum.Obtain 1500 mg (81% of theoretical value) target compound.
LC/MS [method 1]: R t=2.05 min; MS [ESIpos]: m/z=344 and 346 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 1.35 (t, 3H), 4.41 (q, 2H), 5.96 (s, 2H), 7.53 (dd, 1H), 7.59-7.64 (m, 2H), 7.96 (s, 1H)。
Embodiment 34A
1-(2-chloro-phenyl-)-1 h-imidazoles-4-methyl-formiate
By 200 mg (1.59 mmol) 1 h-imidazoles-4-methyl-formiate, 496 mg (3.17 mmol) 2-chlorophenylboronic acid, 100 mg 3 molecular sieves and 432 mg (2.28 mmol) venus crystals (II) put into 2 ml methylene dichloride in advance, and add 256 μ l (3.17 mmol) pyridine.By described mixture at stirring at room temperature 20 h.In order to carry out aftertreatment, by mixture described in a small amount of diatomite filtration, with about 15 ml ethyl acetate rinse filter residues, and with the filtrate of 5 ml water washings merging.Organic phase, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 3:1 → 1:1 → 1:3), purification of crude product.Obtain 55 mg (13% of theoretical value) target compound.
LC/MS [method 3]: R t=0.90 min; MS [ESIpos]: m/z=237 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.79 (s, 3H), 7.53-7.58 (m, 2H), 7.64 (dd, 1H), 7.70-7.77 (m, 1H), 8.05 (d, 1H), 8.20 (d, 1H)。
Embodiment 35A
1-(2-chloro-phenyl-)-1 h-pyrazoles-4-ethyl formate
By 400 mg (2.85 mmol) 1 h-pyrazoles-4-ethyl formate, 893 mg (5.71 mmol) 2-chlorophenylboronic acid, 100 mg 3 molecular sieves and 778 mg (4.28 mmol) venus crystals (II) put into 2 ml methylene dichloride in advance, and add 461 μ l (5.71 mmol) pyridine.By described mixture at stirring at room temperature 20 h.In order to carry out aftertreatment, by mixture described in a small amount of diatomite filtration, with about 10 ml dichloromethane rinse filter residues, and the filtrate of concentrated merging in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 10:1, then 5:1), purification of crude product.Obtain 71 mg (10% of theoretical value) target compound.
LC/MS [method 3]: R t=1.15 min; MS [ESIpos]: m/z=251 (M+H) +.
Embodiment 36A
[1-(2,6-dichloro benzyl)-1 h-imidazoles-5-base] methyl alcohol
220 mg (0.74 mmol) are derived from the compound dissolution of embodiment 32A in 3 ml THF, and drip the 1 M solution of 0.74 ml (0.74 mmol) lithium aluminum hydride in THF at 0 DEG C.By described mixture at stirring at room temperature 1 h.In order to carry out aftertreatment, adding the saturated potassium sodium tartrate solution of 5 ml under ice-cooling, with mixture described in 10 ml diluted ethyl acetate, and leaching the solid of precipitation.By chromatography [method 19] purification of crude product.Obtain 188 mg (99% of theoretical value) target compound.
LC/MS [method 3]: R t=0.51 min; MS [ESIpos]: m/z=257 and 259 (M+H) +.
Embodiment 37A
[1-(2,6-dichloro benzyl)-4-nitro-1 h-imidazoles-2-base] methyl alcohol
The compound 1200 mg (3.5 mmol) being derived from embodiment 33A is dissolved in 53 ml 1 together with 15 mg (0.35 mmol) lithium chloride, in 2-glycol dimethyl ether, and add 198 mg (5.23 mmol) sodium borohydride at 0 DEG C.By described mixture at stirring at room temperature 1 h.In order to carry out aftertreatment, add the saturated potassium sodium tartrate solution of 25 ml under ice-cooling, and with mixture described in 50 ml extraction into ethyl acetate.Organic phase, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: ethyl acetate/hexanaphthene 1:1), purification of crude product.Obtain 800 mg (76% of theoretical value) target compound.
LC/MS [method 5]: R t=1.82 min; MS [ESIpos]: m/z=302 and 304 (M+H) +.
Embodiment 38A
[1-(2-chloro-phenyl-)-1 h-imidazol-4 yl] methyl alcohol
50 mg (0.21 mmol) are derived from the compound dissolution of embodiment 34A in 1 ml THF, and add the 1 N solution of 222 μ l (0.22 mmol) lithium aluminum hydride in THF at-10 DEG C.Then described mixture was heated to room temperature in 1 hour.In order to carry out aftertreatment, add 2 ml water and the saturated potassium sodium tartrate solution of 5 ml, and with mixture described in each 10 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.Obtain 34 mg (56% of theoretical value) target compound, purity is 73%.
LC/MS [method 3]: R t=0.34 min; MS [ESIpos]: m/z=209 (M+H) +.
Embodiment 39A
[1-(2-chloro-phenyl-)-1 h-pyrazoles-4-base] methyl alcohol
80 mg (0.32 mmol) are derived from the compound dissolution of embodiment 35A in 2 ml THF, and add the 1 N solution of 335 μ l (0.34 mmol) lithium aluminum hydride in THF at-10 DEG C.Then described mixture was heated to room temperature in 1 hour.In order to carry out aftertreatment, add 2 ml water and the saturated potassium sodium tartrate solution of 5 ml, and with mixture described in each 10 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.Obtain 61 mg (83% of theoretical value) target compound, purity is 91%.
LC/MS [method 3]: R t=0.76 min; MS [ESIpos]: m/z=209 (M+H) +.
Embodiment 40A
5-(chloromethyl)-1-(2,6-dichloro benzyl)-1 h-imidazoles
The compound 45 mg (0.18 mmol) being derived from embodiment 36A is dissolved in 1 ml toluene together with 27 mg (0.26 mmol) triethylamine, and drips 25 mg (0.21 mmol) thionyl chloride in room temperature.By described mixture at stirring at room temperature 1 h.In a vacuum, all volatile constituents in described reaction mixture are removed.Obtain 48 mg (99% of theoretical value) target compound, it is without other purifying ground reaction further any.
Embodiment 41A
2-(chloromethyl)-1-(2,6-dichloro benzyl)-4-nitro-1 h-imidazoles
210 mg (0.70 mmol) are derived from the compound dissolution of embodiment 37A in 10 ml methylene dichloride, and add 145 μ l (1.04 mmol) triethylamine and 61 μ l (0.83 mmol) thionyl chloride at 0 DEG C.By described mixture at stirring at room temperature 24 h.Then add other 200 μ l (2.72 mmol) thionyl chloride, and described mixture is stirred 15 min under reflux.In a vacuum, all volatile constituents of described reaction mixture are removed.Obtain 200 mg (80% of the theoretical value) target compound that purity is 88%, it is without other purifying ground reaction further any.
LC/MS [method 3]: R t=1.16 min; MS [ESIpos]: m/z=320 and 322 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 5.03 (s, 2H), 5.61 (s, 2H), 7.52-7.57 (m, 1H), 7.62-7.65 (m, 2H), 7.86-7.88 (m, 1H)。
Embodiment 42A
4-(bromomethyl)-1-(2-chloro-phenyl-)-1 h-imidazoles
48 mg (0.16 mmol) are derived from the compound of embodiment 38A and 63 mg (0.24 mmol) triphenylphosphine dissolved in 1.6 ml THF, and add 80 mg (0.24 mmol) carbon tetrabromide in room temperature.Then by described mixture at stirring at room temperature 16 h.In order to carry out aftertreatment, with mixture described in 20 g diatomite filtrations, use ethyl acetate rinse filter residue, and concentrated filtrate in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 5:1, then 1:1) Purification.Obtain 17 mg (39% of theoretical value) target compound, it is immediately for further reaction.
LC/MS [method 4]: R t=0.34 min; MS [ESIpos]: m/z=209 (M-Br+OH+H) +.
Embodiment 43A
4-(bromomethyl)-1-(2-chloro-phenyl-)-1 h-pyrazoles
61 mg (0.27 mmol) are derived from the compound of embodiment 39A and 105 mg (0.40 mmol) triphenylphosphine dissolved in 1.6 ml THF, and add 132 mg (0.40 mmol) carbon tetrabromide in room temperature.Then by described mixture at stirring at room temperature 16 h.In order to carry out aftertreatment, with mixture described in 20 g diatomite filtrations, use ethyl acetate rinse filter residue, and concentrated filtrate in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 10:1, then 5:1) Purification.Obtain 30 mg (42% of theoretical value) target compound, it is immediately for further reaction.
LC/MS [method 4]: R t=0.67 min; MS [ESIpos]: m/z=209 (M-Br+OH+H) +.
Embodiment 44A
2-(2-chloro-phenyl-)-1,3-oxazole-5-ethyl formate
Under argon, by 300 mg (1.71 mmol) 2-bromo-1,3-oxazole-5-ethyl formate is dissolved in 7 ml toluene together with 422 mg (2.56 mmol) 2-chlorophenylboronic acid, and add successively 67 mg (0.17 mmol) 2-dicyclohexyl phosphino--2'-( n,N-dimethylamino) biphenyl, 78 mg (0.085 mmol) three (dibenzalacetone) two palladium and 725 mg (3.42 mmol) potassiumphosphate.Described mixture is heated to 110 DEG C, and stirs 20 h in this temperature.In order to carry out aftertreatment, described reaction mixture is cooled to room temperature, and dilutes with 20 ml ethyl acetate and 20 ml water.After being separated, also use each 20 ml extraction into ethyl acetate aqueous phase 2 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By preparation HPLC [method 19] Purification.Obtain 217 mg (50% of theoretical value) target compound.
LC/MS [method 3]: R t=1.21 min; MS [ESIpos]: m/z=252 (M+H) +.
Embodiment 45A
2-(2,3-dichlorophenyl)-1,3-oxazole-5-ethyl formate
Bromo-1, the 3-oxazole-5-ethyl formate of 300 mg (1.71 mmol) 2-is reacted similarly with the method in embodiment 44A.Obtain 174 mg (31% of theoretical value) target compound, purity is 87%.
LC/MS [method 4]: R t=1.19 min; MS [ESIpos]: m/z=286 and 288 (M+H) +.
Embodiment 46A
5-(2-chloro-phenyl-) thiophene-2-carboxylic acid methyl esters
Under argon, 310 mg (1.40 mmol) 5-bromothiophene-2-methyl-formiate is dissolved in 10 ml dioxs together with 328 mg (2.10 mmol) 2-chlorophenylboronic acid, and adds 81 mg (0.07 mmol) tetrakis triphenylphosphine palladium (0).Described mixture is heated to 110 DEG C, adds 1.4 ml (2.80 mmol) 2 M aqueous sodium carbonate, and described mixture is stirred 20 h in this temperature.In order to carry out aftertreatment, described reaction mixture is cooled to room temperature, and dilutes with 20 ml ethyl acetate and 20 ml water.After being separated, also use each 20 ml extraction into ethyl acetate aqueous phase 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 15:1, then 10:1) Purification.Obtain 289 mg (61% of theoretical value) target compound, purity is 75%.
LC/MS [method 2]: R t=2.58 min; MS [ESIpos]: m/z=253 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.85 (s, 3H), 7.45-7.48 (m, 2H), 7.53 (d, 1H), 7.64 (dd, 1H), 7.73 (dd, 1H), 7.85 (d, 1H)。
Embodiment 47A
5-(2,3-dichlorophenyl) thiophene-2-carboxylic acid methyl esters
300 mg (1.36 mmol) 5-bromothiophene-2-methyl-formiate is reacted similarly with the method in embodiment 46A.Obtain 273 mg (58% of theoretical value) target compound, purity is 83%.
LC/MS [method 4]: R t=1.30 min; MS [ESIpos]: m/z=287 (M+H) +.
Embodiment 48A
5-(2-chloro-phenyl-) thiophene-2-carboxylic acid
289 mg (1.14 mmol) are derived from the compound dissolution of embodiment 46A in 2 ml THF/ methyl alcohol (1:1), and add 1.14 ml (2.29 mmol) 2 M aqueous sodium hydroxide solution.Described reaction mixture is stirred 2 h at 80 DEG C.After being cooled to room temperature, on the rotary evaporator except desolventizing, and resistates is dissolved in 5 ml water, and washs by 5 ml ethyl acetate.With 1 N hcl acidifying aqueous phase, and with each 5 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.Obtain 218 mg (73% of the theoretical value) target compound that purity is 91%.
LC/MS [method 2]: R t=2.16 min; MS [ESIpos]: m/z=239 (M+H) +.
Embodiment 49A
5-(2,3-dichlorophenyl) thiophene-2-carboxylic acid
The compound that 273 mg (0.79 mmol) derive from embodiment 47A is reacted similarly with the method in embodiment 48A.Obtain 228 mg (97% of the theoretical value) target compound that purity is 92%.
LC/MS [method 4]: R t=1.07 min; MS [ESIpos]: m/z=271 and 273 (M-H) -.
Embodiment 50A
[2-(2-chloro-phenyl-)-1,3-oxazole-5-base] methyl alcohol
The compound that 217 mg (0.86 mmol) derive from embodiment 44A is reacted similarly with the method in embodiment 39A.Obtain 181 mg (89% of the theoretical value) target compound that purity is 89%.
LC/MS [method 4]: R t=0.75 min; MS [ESIpos]: m/z=210 (M+H) +.
Embodiment 51A
[2-(2,3-dichlorophenyl)-1,3-oxazole-5-base] methyl alcohol
With the method in embodiment 39A similarly, react the compound that 186 mg (0.65 mmol) derive from embodiment 45A.Obtain 89 mg (48% of the theoretical value) target compound that purity is 86%.
LC/MS [method 4]: R t=0.87 min; MS [ESIpos]: m/z=244 and 246 (M+H) +.
Embodiment 52A
[5-(2-chloro-phenyl-)-2-thienyl] methyl alcohol
350 mg (1.47 mmol) are derived from the compound dissolution of embodiment 48A in 5 ml THF, described mixture is cooled to 0 DEG C, and adds 0.20 ml (1.47 mmol) triethylamine and 0.21 ml (1.61 mmol) isobutyl chlorocarbonate.Described mixture is stirred 1 h at 0 DEG C.Then by match thatch frit (Seitz-Fritte), suspension filtered is entered to be cooled in the flask of 0 DEG C, and rinse filter residue with about 2 ml THF.Then, with vigorous stirring, filtrate the adding obtained is cooled in the solution of 166 mg (4.40 mmol) sodium borohydride in 2 ml water of 0 DEG C.After 1 h, add 5 ml saturated sodium bicarbonate solutions, and described mixture is heated to room temperature.With mixture described in 15 ml extraction into ethyl acetate.Successively by each 5 ml saturated sodium bicarbonate solutions and saturated nacl aqueous solution washing organic phase.After dried over sodium sulfate, filter described mixture, and concentrate in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 10:1, then 5:1) purification of crude product.Obtain 252 mg (63% of theoretical value) title compound, purity is 83%.
LC/MS [method 3]: R t=1.12 min; MS [ESIpos]: m/z=206 (M-H 2o+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 4.66 (d, 2H), 5.54 (t, 1H), 6.99 (d, 1H), 7.27 (d, 1H), 7.33-7.43 (m, 2H), 7.55-7.62 (m, 2H)。
Embodiment 53A
[5-(2,3-dichlorophenyl)-2-thienyl] methyl alcohol
With the method in embodiment 52A similarly, react the compound that 268 mg (0.98 mmol) derive from embodiment 49A.Obtain 184 mg (63% of the theoretical value) target compound that purity is 87%.
LC/MS [method 4]: R t=1.10 min; MS [ESIpos]: m/z=241 and 243 (M-H 2o+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 4.67 (d, 2H), 5.58 (t, 1H), 7.01 (d, 1H), 7.29 (d, 1H), 7.39-7.44 (m, 1H), 7.55-7.58 (m, 1H), 7.62-7.66 (m, 1H)。
Embodiment 54A
5-(bromomethyl)-2-(2-chloro-phenyl-)-1,3-oxazole
181 mg (0.77 mmol) are derived from the compound of embodiment 50A and 242 mg (0.92 mmol) triphenylphosphine dissolved in 4 ml THF, and add 306 mg (0.92 mmol) carbon tetrabromide in room temperature.Then by described mixture at stirring at room temperature 16 h.In order to carry out aftertreatment, with mixture described in 20 g diatomite filtrations, use ethyl acetate rinse filter residue, and concentrated filtrate in a vacuum.By preparation HPLC [method 19] Purification.Obtaining 112 mg (42% of theoretical value) purity is the target compound of 80%, and it reacts immediately further.
LC/MS [method 4]: R t=1.09 min; MS [ESIpos]: m/z=272 and 274 (M+H) +.
Embodiment 55A
5-(bromomethyl)-2-(2,3-dichlorophenyl)-1,3-oxazole
With the method in embodiment 54A similarly, react the compound that 89 mg (0.31 mmol) derive from embodiment 51A.Obtain 50 mg (52% of the theoretical value) target compound that purity is 87%.
LC/MS [method 4]: R t=1.15 min; MS [ESIpos]: m/z=308 (M+H) +.
Embodiment 56A
2-(bromomethyl)-5-(2-chloro-phenyl-) thiophene
200 mg (0.74 mmol) are derived from the compound of embodiment 52A and 291 mg (1.11 mmol) triphenylphosphine dissolved in 8 ml THF, and add 367 mg (1.11 mmol) carbon tetrabromide in room temperature.Then by described mixture at stirring at room temperature 16 h.In order to carry out aftertreatment, with mixture described in 20 g diatomite filtrations, use ethyl acetate rinse filter residue, and concentrated filtrate in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 10:1, then 5:1) Purification.It reacts immediately further to obtain the contaminated target product of 113 mg (32% is pure, 17% of theoretical value).
LC/MS [method 4]: R t=1.37 min; MS [ESIpos]: m/z=207 (M-HBr) +.
Embodiment 57A
2-(bromomethyl)-5-(2,3-dichlorophenyl) thiophene
With the method in embodiment 56A similarly, react the compound that 89 mg (0.31 mmol) derive from embodiment 53A.Obtain 70 mg (30% of the theoretical value) target compound that purity is 86%.
LC/MS [method 4]: R t=1.08 min; MS [ESIpos]: m/z=241 and 243 (M-HBr) +.
Embodiment 58A
2-[2-(trifluoromethyl) phenyl] iso methyl nicotinate
Under an argon, 500 mg (2.31 mmol) 2-bromine isonicotinic acid methyl esters and 694 mg (3.47 mmol) 2-(trifluoromethyl) phenyl-boron dihydroxide are dissolved in 10 ml toluene.Then add 106 mg (0.12 mmol) three (dibenzalacetone) two palladium, 91 mg (0.23 mmol) tri-butyl phosphine and 982 mg (4.63 mmol) potassiumphosphate, and described mixture is heated to 110 DEG C under argon and continues 20 h.In order to carry out aftertreatment, diluting described mixture at room temperature 15 ml ethyl acetate and 15 ml water, isolating organic phase, and also use each 15 ml extraction into ethyl acetate aqueous phase 2 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 20:1, then 10:1) purification of crude product.Obtain 498 mg (59% of theoretical value) target compound, purity is 77%.According to method 19, be further purified second product fraction with more low-purity.Obtain other 54 mg (8% of theoretical value) target compound.
LC/MS [method 2]: R t=2.21 min; MS [ESIpos]: m/z=282 (M+H) +.
Embodiment 59A
2-(2-chloro-phenyl-) iso methyl nicotinate
With the method in embodiment 58A similarly, 500 mg (2.31 mmol) 2-bromine isonicotinic acid methyl esters and 597 mg (3.47 mmol) 2-chlorophenylboronic acid are reacted each other.Obtain 323 mg (56% of theoretical value) target compound.
LC/MS [method 3]: R t=1.15 min; MS [ESIpos]: m/z=248 (M+H) +.
Embodiment 60A
2-(2,3-dichlorophenyl) iso methyl nicotinate
Under an argon, 250 mg (1.16 mmol) 2-bromine isonicotinic acid methyl esters and 331 mg (1.74 mmol) 2,3-dichlorophenyl boric acid are dissolved in 5 ml toluene.Then add 53 mg (0.06 mmol) three (dibenzalacetone) two palladium, 46 mg (0.12 mmol) 2-dicyclohexyl phosphino--2'-( n,N-dimethylamino) biphenyl and 491 mg (2.31 mmol) potassiumphosphate, and described mixture is heated to 110 DEG C under argon and continues 20 h.In order to carry out aftertreatment, diluting described mixture at room temperature 15 ml ethyl acetate and 15 ml water, isolating organic phase, and also use each 15 ml extraction into ethyl acetate aqueous phase 2 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 138 mg (42% of theoretical value) target compound, purity is 87%.
LC/MS [method 4]: R t=1.13 min; MS [ESIpos]: m/z=282 and 284 (M+H) +.
Embodiment 61A
{ 2-[2-(trifluoromethyl) phenyl] pyridin-4-yl } methyl alcohol
432 mg (1.54 mmol) are derived from the compound dissolution of embodiment 58A in 10 ml THF, and add the 1 M solution of 1.08 ml (1.08 mmol) lithium aluminum hydride in THF at-10 DEG C.After the addition has been completed, by described mixture at stirring at room temperature 2 h.In order to carry out aftertreatment, add the saturated potassium sodium tartrate solution of 4 ml in room temperature, and with mixture described in 15 ml extraction into ethyl acetate.Wash organic phase 1 time with the saturated potassium sodium tartrate solution of 10 ml, through dried over mgso, filter, and concentrate in a vacuum.Obtain 497 mg (>100% theoretical value) target compound, it is without other purifying ground reaction further any.
LC/MS [method 2]: R t=1.40 min; MS [ESIpos]: m/z=254 (M+H) +.
Embodiment 62A
[2-(2-chloro-phenyl-) pyridin-4-yl] methyl alcohol
With the method in embodiment 61A similarly, react the compound that 323 mg (1.24 mmol) derive from embodiment 59A.Obtain 303 mg (>100% theoretical value) target compound, it is without other purifying ground reaction further any.
1H-NMR (400 MHz, DMSO-d 6): δ= 4.61 (d, 2H), 5.47 (t, 1H), 7.33-7.37 (m, 1H), 7.42-7.48 (m, 2H), 7.53-7.60 (m, 3H), 8.61 (d, 1H)。
Embodiment 63A
[2-(2,3-dichlorophenyl) pyridin-4-yl] methyl alcohol
With the method in embodiment 61A similarly, react the compound that 138 mg (0.49 mmol) derive from embodiment 60A.Obtain 132 mg (90% of theoretical value) target compound, purity is 84%, and it is without other purifying ground reaction further any.
LC/MS [method 2]: R t=0.78 min; MS [ESIpos]: m/z=254 and 256 (M+H) +.
Embodiment 64A
4-(bromomethyl)-2-[2-(trifluoromethyl) phenyl] pyridine
495 mg (1.96 mmol) are derived from the compound of embodiment 61A and 615 mg (2.35 mmol) triphenylphosphine dissolved in 15 ml THF, and add 778 mg (2.35 mmol) carbon tetrabromide in room temperature.After the addition has been completed, by described mixture at stirring at room temperature 16 h.In order to carry out aftertreatment, with mixture described in 20 g diatomite filtrations, and concentrated filtrate in a vacuum.By chromatography on silica gel (elutriant: first use cyclohexane/ethyl acetate 70:30, then uses ethyl acetate) Purification.Obtain 149 mg (22% of the theoretical value) target compound that purity is 90%, it reacts immediately further.
LC/MS [method 3]: R t=1.23 min; MS [ESIpos]: m/z=318 (M+H) +.
Embodiment 65A
4-(bromomethyl)-2-(2-chloro-phenyl-) pyridine
With the method in embodiment 64A similarly, react the compound that 294 mg (1.34 mmol) derive from embodiment 62A.Obtain 242 mg (57% of the theoretical value) target compound that purity is 89%, it reacts immediately further.
LC/MS [method 4]: R t=1.08 min; MS [ESIpos]: m/z=282 and 284 (M+H) +.
Embodiment 66A
4-(bromomethyl)-2-(2,3-dichlorophenyl) pyridine
With the method in embodiment 54A similarly, react the compound that 131 mg (0.52 mmol) derive from embodiment 63A.Obtain 81 mg (50% of theoretical value) target compound, it reacts immediately further.
LC/MS [method 4]: R t=1.08 min; MS [ESIpos]: m/z=316,318 and 320 (M+H) +.
Embodiment 67A
4-methyl-2-[2-(trifluoromethyl) phenyl] pyrimidine
Under an argon, the chloro-4-methylpyrimidine of 250 mg (1.95 mmol) 2-and 583 mg (2.92 mmol) 2-(trifluoromethyl) phenyl-boron dihydroxide are dissolved in 8 ml toluene.Then add 89 mg (0.10 mmol) three (dibenzalacetone) two palladium, 77 mg (0.19 mmol) 2-dicyclohexyl phosphino--2'-( n,N-dimethylamino) biphenyl and 826 mg (3.89 mmol) potassiumphosphate, and under argon by described mixture at 110 DEG C of heating 20 h.In order to carry out aftertreatment, diluting described mixture at room temperature 15 ml ethyl acetate and 15 ml water, isolating organic phase, and also use each 15 ml extraction into ethyl acetate aqueous phase 2 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 9:1, then 4:1) purification of crude product.Obtain 249 mg (54% of theoretical value) target compound, purity is 87%.
LC/MS [method 3]: R t=1.02 min; MS [ESIpos]: m/z=239 (M+H) +.
Embodiment 68A
2-(2-chloro-phenyl-)-4-methylpyrimidine
With the method in embodiment 67A similarly, react the chloro-4-methylpyrimidine of 250 mg (1.95 mmol) 2-.Obtain 202 mg (34% of theoretical value) target compound, purity is 66%.
LC/MS [method 3]: R t=0.90 min; MS [ESIpos]: m/z=205 (M+H) +.
Embodiment 69A
4-methyl-6-[2-(trifluoromethyl) phenyl] pyrimidine
With the method in embodiment 67A similarly, react the chloro-6-methylpyrimidine of 250 mg (1.95 mmol) 4-.Obtain 332 mg (70% of theoretical value) target compound.
LC/MS [method 3]: R t=1.04 min; MS [ESIpos]: m/z=239 (M+H) +.
Embodiment 70A
4-methyl-6-[2-chloro-phenyl-] pyrimidine
With the method in embodiment 67A similarly, react the chloro-6-methylpyrimidine of 250 mg (1.95 mmol) 4-.Obtain 191 mg (43% of theoretical value) target compound.
LC/MS [method 3]: R t=0.99 min; MS [ESIpos]: m/z=205 (M+H) +.
Embodiment 71A
4-(2,3-dichlorophenyl)-6-methylpyrimidine
With the method in embodiment 67A similarly, react the chloro-6-methylpyrimidine of 250 mg (1.95 mmol) 4-.Obtain 185 mg (40% of theoretical value) target compound.
LC/MS [method 6]: R t=1.93 min; MS [ESIpos]: m/z=239 and 241 (M+H) +.
Embodiment 72A
2-methyl-5-[2-(trifluoromethyl) phenyl]-1,3,4-thiadiazoles
With the method in embodiment 67A similarly, react the bromo-5-methyl isophthalic acid of 500 mg (1.95 mmol) 2-, 3,4-thiadiazoles.Obtain 331 mg (36% of theoretical value) target compound, purity is 75%.
LC/MS [method 4]: R t=0.93 min; MS [ESIpos]: m/z=245 (M+H) +.
Embodiment 73A
2-(2-chloro-phenyl-)-5-methyl isophthalic acid, 3,4-thiadiazoles
With the method in embodiment 44A similarly, react the bromo-5-methyl isophthalic acid of 315 mg (1.76 mmol) 2-, 3,4-thiadiazoles.Obtain 155 mg (36% of theoretical value) target compound.
LC/MS [method 4]: R t=0.92 min; MS [ESIpos]: m/z=211 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 2.82 (s, 3H), 7.52-7.62 (m, 2H), 7.70 (dd, 1H), 8.10 (dd, 1H)。
Embodiment 74A
2-(2,3-dichlorophenyl)-5-methyl isophthalic acid, 3,4-thiadiazoles
With the method in embodiment 44A similarly, react the bromo-5-methyl isophthalic acid of 310 mg (1.73 mmol) 2-, 3,4-thiadiazoles.Obtain 91 mg (21% of theoretical value) target compound.
LC/MS [method 6]: R t=2.13 min; MS [ESIpos]: m/z=245 and 247 (M+H) +.
Embodiment 75A
5-(2-chloro-phenyl-)-2-methyl isophthalic acid, 3-thiazole
With the method in embodiment 67A similarly, react the bromo-2-methyl isophthalic acid of 756 mg (2.92 mmol) 5-, 3-thiazole-hydrogen bromide.In the reaction, use 2.49 g (11.68 mmol) potassiumphosphate as alkali.Obtain 181 mg (30% of theoretical value) target compound.
LC/MS [method 2]: R t=2.21 min; MS [ESIpos]: m/z=210 (M+H) +.
Embodiment 76A
2-methyl-5-[2-(trifluoromethyl) phenyl]-1,3-thiazoles
With the method in embodiment 44A similarly, react the bromo-2-methyl isophthalic acid of 430 mg (1.66 mmol) 5-, 3-thiazole-hydrogen bromide.In the reaction, use 1.41 g (6.64 mmol) potassiumphosphate as alkali.Obtain 52 mg (13% of theoretical value) target compound.
LC/MS [method 4]: R t=1.08 min; MS [ESIpos]: m/z=244 (M+H) +.
Embodiment 77A
5-(the chloro-2-fluorophenyl of 3-)-2-methyl isophthalic acid, 3-thiazole
With the method in embodiment 44A similarly, react the bromo-2-methyl isophthalic acid of 586 mg (2.26 mmol) 5-, 3-thiazole-hydrogen bromide.In the reaction, use 1.92 g (9.05 mmol) potassiumphosphate as alkali.Obtain 147 mg (29% of theoretical value) target compound.
LC/MS [method 3]: R t=1.27 min; MS [ESIpos]: m/z=228 (M+H) +.
Embodiment 78A
5-[the fluoro-3-of 2-(trifluoromethyl) phenyl]-2-methyl isophthalic acid, 3-thiazole
With the method in embodiment 44A similarly, react the bromo-2-methyl isophthalic acid of 350 mg (1.35 mmol) 5-, 3-thiazole-hydrogen bromide.In the reaction, use 1.15 g (5.41 mmol) potassiumphosphate as alkali.Reaction times is 2 h.Obtain 89 mg (25% of theoretical value) target compound.
LC/MS [method 4]: R t=1.12 min; MS [ESIpos]: m/z=262 (M+H) +.
Embodiment 79A
5-(2-chloro-phenyl-)-2-methyl-4-(trifluoromethyl)-1,3-thiazoles
With the method in embodiment 44A similarly, react 635 mg (1.94 mmol) 5-bromo-2-methyl-4-(trifluoromethyl)-1,3-thiazoles-hydrogen bromide.In the reaction, use 1.15 g (5.41 mmol) potassiumphosphate as alkali.Obtain 142 mg (26% of theoretical value) target compound.
LC/MS [method 3]: R t=1.34 min; MS [ESIpos]: m/z=278 (M+H) +.
Embodiment 80A
4-(bromomethyl)-2-[2-(trifluoromethyl) phenyl] pyrimidine
247 mg (1.04 mmol) are derived from compound and 185 mg (1.04 mmol) of embodiment 67A n-bromine succinimide and 17 mg (0.10 mmol) 2,2'-azo two-2-methyl propionitrile heat 18 h under reflux together in 3 ml tetracol phenixin.In order to carry out aftertreatment, described reaction mixture is cooled to room temperature, and adds 10 ml methylene dichloride.With mixture described in 5 ml water washings, and return extraction aqueous phase 2 times with each 5 ml methylene dichloride.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.Dry raw product momently under a high vacuum, and without other purifying ground reaction further.Obtain the product that 303 mg contain target compound, purity was 20% (being equivalent to 20% of theoretical value).The main ingredient of described crude product is unreacted raw material (embodiment 67A).
LC/MS [method 4]: R t=1.02 min; MS [ESIpos]: m/z=317 and 319 (M+H) +.
Embodiment 81A
4-(bromomethyl)-2-(2-chloro-phenyl-) pyrimidine
With the method in embodiment 80A similarly, react the compound that 200 mg (0.98 mmol) derive from embodiment 68A.Obtain 259 mg (19% of theoretical value) target compound, purity is about 20%.The main ingredient of described crude product is unreacted raw material (embodiment 68A).
LC/MS [method 4]: R t=1.00 min; MS [ESIpos]: m/z=283 and 285 (M+H) +.
Embodiment 82A
4-(bromomethyl)-6-[2-(trifluoromethyl) phenyl] pyrimidine
With the method in embodiment 80A similarly, react the compound that 332 mg (1.39 mmol) derive from embodiment 69A.By chromatography [method 19] purification of crude product.Obtain 37 mg (8% of theoretical value) target compound.
LC/MS [method 3]: R t=1.19 min; MS [ESIpos]: m/z=317 and 319 (M+H) +.
Embodiment 83A
4-(bromomethyl)-6-[2-chloro-phenyl-] pyrimidine
With the method in embodiment 80A similarly, react the compound that 191 mg (0.93 mmol) derive from embodiment 70A.By chromatography [method 19] purification of crude product.Obtain 27 mg (10% of theoretical value) target compound.
LC/MS [method 3]: R t=1.15 min; MS [ESIpos]: m/z=283 and 285 (M+H) +.
Embodiment 84A
4-(bromomethyl)-6-(2,3-dichlorophenyl) pyrimidine
With the method in embodiment 80A similarly, react the compound that 185 mg (0.93 mmol) derive from embodiment 71A.By chromatography [method 19] purification of crude product.Obtain 23 mg (9% of theoretical value) target compound.
LC/MS [method 6]: R t=2.32 min; MS [ESIpos]: m/z=317,319 and 321 (M+H) +.
Embodiment 85A
2-(bromomethyl)-5-[2-(trifluoromethyl) phenyl]-1,3,4-thiadiazoles
172 mg (0.70 mmol) are derived from compound and 251 mg (1.41 mmol) of embodiment 72A n-bromine succinimide and 12 mg (0.07 mmol) 2,2'-azo two-2-methyl propionitrile heat 8 h under reflux together in 5 ml tetracol phenixin.In order to carry out aftertreatment, described reaction mixture is cooled to room temperature, and adds 10 ml methylene dichloride.With mixture described in 5 ml water washings, and return extraction aqueous phase 2 times with each 5 ml methylene dichloride.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 33 mg (15% of theoretical value) target compound.
LC/MS [method 4]: R t=1.05 min; MS [ESIpos]: m/z=323 and 325 (M+H) +.
Embodiment 86A
2-(bromomethyl)-5-(2-chloro-phenyl-)-1,3,4-thiadiazoles
With the method in embodiment 85A similarly, react the compound that 185 mg (0.88 mmol) derive from embodiment 73A.By chromatography [method 19] purification of crude product.Obtain 31 mg (12% of theoretical value) target compound.
LC/MS [method 6]: R t=2.21 min; MS [ESIpos]: m/z=289 and 291 (M+H) +.
Embodiment 87A
2-(bromomethyl)-5-(2,3-dichlorophenyl)-1,3,4-thiadiazoles
With the method in embodiment 85A similarly, react the compound that 91 mg (0.37 mmol) derive from embodiment 74A.By chromatography [method 19] purification of crude product.Obtain 38 mg (32% of theoretical value) target compound.
LC/MS [method 3]: R t=1.30 min; MS [ESIpos]: m/z=323,325 and 327 (M+H) +.
Embodiment 88A
2-(bromomethyl)-5-(2-chloro-phenyl-)-1,3-thiazoles
180 mg (0.86 mmol) are derived from compound and 229 mg (1.29 mmol) of embodiment 75A n-bromine succinimide and 14 mg (0.09 mmol) 2,2'-azo two-2-methyl propionitrile heat 8 h under reflux together in 5 ml tetracol phenixin.In order to carry out aftertreatment, described reaction mixture is cooled to room temperature, and adds 10 ml methylene dichloride.With mixture described in 5 ml water washings, and return extraction aqueous phase 2 times with each 5 ml methylene dichloride.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 66 mg (27% of theoretical value) target compound.
LC/MS [method 2]: R t=2.42 min; MS [ESIpos]: m/z=288 and 290 (M+H) +.
Embodiment 89A
2-(bromomethyl)-5-[2-(trifluoromethyl) phenyl]-1,3-thiazoles
With the method in embodiment 88A similarly, react the compound that 110 mg (0.45 mmol) derive from embodiment 76A.By chromatography [method 19] purification of crude product.Obtain 40 mg (27% of theoretical value) target compound.
LC/MS [method 4]: R t=1.17 min; MS [ESIpos]: m/z=322 and 324 (M+H) +.
Embodiment 90A
2-(bromomethyl)-5-(the chloro-2-fluorophenyl of 3-)-1,3-thiazoles
With the method in embodiment 88A similarly, react the compound that 142 mg (0.62 mmol) derive from embodiment 77A.By chromatography [method 19] purification of crude product.Obtain 70 mg (37% of theoretical value) target compound.
LC/MS [method 4]: R t=1.21 min; MS [ESIpos]: m/z=306 and 308 (M+H) +.
Embodiment 91A
2-(bromomethyl)-5-[the fluoro-3-of 2-(trifluoromethyl) phenyl]-1,3-thiazoles
With the method in embodiment 88A similarly, react the compound that 120 mg (0.46 mmol) derive from embodiment 78A.By chromatography [method 19] purification of crude product.Obtain 60 mg (38% of theoretical value) target compound.
LC/MS [method 4]: R t=1.20 min; MS [ESIpos]: m/z=340 and 342 (M+H) +.
Embodiment 92A
2-(bromomethyl)-5-(2-chloro-phenyl-)-4-(trifluoromethyl)-1,3-thiazoles
With the method in embodiment 88A similarly, react the compound that 140 mg (0.50 mmol) derive from embodiment 79A.By chromatography [method 19] purification of crude product.Obtain 49 mg (27% of theoretical value) target compound.
LC/MS [method 4]: R t=1.27 min; MS [ESIpos]: m/z=356 and 358 (M+H) +.
Embodiment 93A
5-(4-chloro-phenyl-)-4-cyclopropyl-2-(1 h-1,2,4-triazole-5-base alkylsulfonyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
By 300 mg (1.27 mmol) 5-(4-chloro-phenyl-)-4-cyclopropyl-2,4-dihydro-3 h-1,2,4-triazole-3-ketone [preparing according to WO 2007/134862 embodiment 36A] is dissolved in 10 ml THF, and adds 143 mg (1.27 mmol) potassium tert.-butoxide at-78 DEG C.In 30 min, described reaction mixture is heated to room temperature, and described mixture is stirred other 20 min in this temperature.Then described mixture is cooled to-78 DEG C again, and adds 213 mg (1.27 mmol) 1 be dissolved in 5 ml THF h-1,2,4-triazole-5-SULPHURYL CHLORIDE.In 30 min, described reaction mixture is heated to room temperature, and described mixture is stirred other 20 h in this temperature.In order to carry out aftertreatment, add 10 ml water.With mixture described in each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 136 mg (29% of theoretical value) target compound.
LC/MS [method 5]: R t=1.91 min; M/z=367 (M+H) +.
Embodiment 94A
5-(4-chloro-phenyl-)-4-(4-methoxy-benzyl)-2-(1 h-1,2,4-triazole-5-base alkylsulfonyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
By 529 mg (1.68 mmol) 5-(4-chloro-phenyl-)-4-(4-methoxy-benzyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone [preparing according to WO 2007/134862 embodiment 55A] is dissolved in 10 ml acetonitriles, and adds 1.09 g (3.35 mmol) cesium carbonate successively and be dissolved in 281 mg (1.68 mmol) 1 in 5 ml acetonitriles h-1,2,4-triazole-5-SULPHURYL CHLORIDE.By described reaction mixture at stirring at room temperature 90 min.In order to carry out aftertreatment, add 10 g silica gel, and in a vacuum except desolventizing.By chromatography on silica gel (then elutriant: first use ethyl acetate uses methylene chloride/methanol 90:10 → 80:20), purifying is adsorbed on the crude product on silica gel.Obtain 268 mg (32% of theoretical value) target compound.
LC/MS [method 5]: R t=2.21 min; M/z=447 (M+H) +.
Embodiment 95A
5-(4-chloro-phenyl-)-2-({ 1-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazole-5-base } alkylsulfonyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
230 mg (0.38 mmol) are derived from the compound dissolution of embodiment 116 in 5 ml acetonitriles, and add 417 mg (0.76 mmol) cerous nitrate (IV) ammonium be dissolved in 5 ml water.Then described mixture is stirred 20 h at 70 DEG C.In order to carry out aftertreatment, concentrated described mixture in a vacuum, and resistates being dissolved in 15 ml water, and with each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: methylene chloride/methanol 99:1 → 90:10) purification of crude product.Obtain 130 mg (70% of theoretical value) target compound.
LC/MS [method 3]: R t=1.22 min; M/z=485 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 5.59 (s, 2H), 7.38 (d, 1H), 7.44 (d, 2H), 7.45-7.55 (m, 2H), 7.70 (d, 1H), 7.81 (d, 2H), 8.12 (s, 1H)。
Embodiment 96A
4-allyl group-5-(4-chloro-phenyl-)-2-[(5-methyl isophthalic acid h-imidazol-4 yl) methyl]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
By 100 mg (0.89 mmol) 4-methylol-5-methyl isophthalic acid h-imidazoles, 252 mg (1.07 mmol) derive from the compound of embodiment 12A and 370 mg (2.68 mmol) salt of wormwood is dissolved in 4.5 ml DMF and 4.5 ml water, and described mixture is stirred 75 min at 200 DEG C in microwave oven.After being cooled to room temperature, in order to carry out aftertreatment, dilute described mixture with 10 ml water, and with each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: first use cyclohexane/ethyl acetate 1:1, then uses methylene chloride/methanol 10:1) purification of crude product.Obtain 153 mg (52% of theoretical value) target compound, purity is 73%.
LC/MS [method 3]: R t=0.82 min; MS [ESIpos]: m/z=330 (M+H) +.
Embodiment 97A
5-(4-chloro-phenyl-)-4-cyclopropyl-2-[(5-methyl isophthalic acid h-imidazol-4 yl) methyl]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
Like the compounds in embodiment 96A, make 181 mg (1.62 mmol) 4-methylol-5-methyl isophthalic acid h-imidazoles, 381 mg (1.62 mmol) 5-(4-chloro-phenyl-)-4-cyclopropyl-2,4-dihydro-3 h-1,2,4-triazole-3-ketone [preparing according to WO 2007/134862 embodiment 36A] and 670 mg (4.85 mmol) salt of wormwood react each other.Obtain 180 mg (47% of theoretical value) target compound, purity is 76%.
LC/MS [method 1]: R t=0.82 min; MS [ESIpos]: m/z=330 (M+H) +.
Embodiment 98A
Bromo [2-(trifluoromethyl) phenyl] ethyl acetate
585 mg (3.89 mmol) sodium bromate is put into 2 ml water in advance, and adds 300 mg (1.29 mmol) 2-(trifluoromethyl) ethyl phenylacetate be dissolved in 2.5 ml ethyl acetate in room temperature.Then the solution of 403 mg (3.89 mmol) sodium bisulfite in 3.8 ml water is added lentamente.By described mixture at stirring at room temperature 18 h.Then the SODIUM HYDROSULPHITE sodium water solution of 5 ml 10% is added.With mixture described in 15 ml extraction into ethyl acetate, and by the hydrogensulfite solution of 5 ml 10% and each 1 time of 5 ml saturated nacl aqueous solutions washing organic phase.Organic phase, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 20:1, then 10:1) purification of crude product.Obtain the mixture (according to GC/MS [method 20], ratio is 16:84) that 186 mg are made up of title compound and raw material 2-(trifluoromethyl) ethyl phenylacetate.According to aforesaid operations, this mixture and 362 mg (2.40 mmol) sodium bromate and 250 mg (2.40 mmol) sodium bisulfite is made to react 1 time again.After aftertreatment, obtain the mixture of 31% title compound and 69% 2-(trifluoromethyl) ethyl phenylacetate, it is without other purifying ground reaction further any.
GC/MS [method 20]: R t=4.28 min; MS [ESIpos]: m/z=237 (M-CO 2c 2h 5) +.
Embodiment 99A
2-(2-bromobenzyl)-5-(4-chloro-phenyl-)-4-cyclopropyl-2,4-dihydro-3 h-1,2,4-triazole-3-ketone
By 1.04 g (4.41 mmol) 5-(4-chloro-phenyl-)-4-cyclopropyl-2,4-dihydro-3 h-1,2,4-triazole-3-ketone [preparing according to WO 2007/134862 embodiment 36A] and 2.16 g (6.62 mmol) cesium carbonate are suspended in 35 ml acetonitriles, and add 1.32 g (5.30 mmol) 2-bromo benzyl bromo.Described mixture is stirred 18 h under reflux.Then the solid of precipitation is filtered out, and concentrated filtrate in a vacuum.In about 50 ml ether, stir remaining solid, then leach, and use a small amount of washed with diethylether.In a vacuum after drying, obtaining 1.05 g (59% of theoretical value) target compound, is white solid.
LC/MS [method 4]: R t=1.19 min; MS [ESIpos]: m/z=404 and 406 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 0.58-0.65 (m, 2H), 0.85-0.93 (m, 2H), 3.20 (tt, 1H), 4.99 (s, 2H), 7.18-7.30 (m, 2H), 7.34-7.41 (m, 1H), 7.56-7.61 (m, 2H), 7.65 (d, 1H), 7.80 (d, 2H)。
Embodiment 100A
2-(the bromo-2-luorobenzyl of 5-)-5-(4-chloro-phenyl-)-4-cyclopropyl-2,4-dihydro-3 h-1,2,4-triazole-3-ketone
By 300 mg (1.27 mmol) 5-(4-chloro-phenyl-)-4-cyclopropyl-2,4-dihydro-3 h-1,2,4-triazole-3-ketone [preparing according to WO 2007/134862 embodiment 36A] and 622 mg (1.91 mmol) cesium carbonate are suspended in 5 ml acetonitriles, and add 536 mg (1.40 mmol) 4-bromo-2-(bromomethyl)-1-fluorobenzene.Described mixture is stirred 18 h under reflux.Then filter out the solid of precipitation, and in a vacuum concentrated filtrate to the volume of about 1.5 ml.After adding 0.5 ml 1 N hydrochloric acid, directly with mixture described in chromatography [method 19] purifying.Obtain 427 mg (56% of theoretical value) target compound, purity is 71%.
LC/MS [method 4]: R t=1.23 min; MS [ESIpos]: m/z=422 and 424 (M+H) +.
Embodiment 101A
2-(3-bromobenzyl)-5-(4-chloro-phenyl-)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound and 635 mg (1.95 mmol) cesium carbonate that 400 mg (1.30 mmol) are derived from embodiment 4A are suspended in 3 ml acetonitriles, and add 357 mg (1.43 mmol) 3-bromo benzyl bromo.Described mixture is stirred 20 h under reflux.Then filter out the solid of precipitation, and in a vacuum concentrated filtrate to the volume of about 1.5 ml, by chromatography [method 19] direct purification.Obtain 507 mg (82% of theoretical value) target compound.
LC/MS [method 4]: R t=1.21 min; MS [ESIpos]: m/z=476 and 478 (M+H) +.
Embodiment 102A
2-(3-bromobenzyl)-5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of embodiment 101A similarly, react the compound that 80 mg (0.26 mmol) derive from embodiment 5A.Obtain 95 mg (76% of theoretical value) target compound.
LC/MS [method 4]: R t=1.21 min; MS [ESIpos]: m/z=476 and 478 (M+H) +.
Embodiment 103A
2-(the bromo-5-luorobenzyl of 3-)-5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of embodiment 101A similarly, react compound and 191 mg (0.71 mmol) 1-bromo-3-(bromomethyl)-5-fluorobenzene that 219 mg (0.71 mmol) derive from embodiment 5A.Obtain 181 mg (51% of theoretical value) target compound.
LC/MS [method 4]: R t=1.24 min; MS [ESIpos]: m/z=494 and 496 (M+H) +.
Embodiment 104A
The bromo-2-{ of 4-[3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl } methyl benzoate
The compound and 715 mg (2.19 mmol) cesium carbonate that 450 mg (1.30 mmol) are derived from embodiment 4A are suspended in 6 ml acetonitriles, and add 708 mg (1.61 mmol) methyl 4-bromo-2-(bromomethyl) benzoic ether.Described mixture is stirred 20 h under reflux.Filter out the solid of precipitation, and in a vacuum concentrated filtrate to the volume of about 1.5 ml.After adding 1 ml 1 N hydrochloric acid, by chromatography [method 19] directly mixture described in purifying.Obtain 545 mg (64% of theoretical value) target compound, purity is 92%.
LC/MS [method 4]: R t=1.24 min; MS [ESIpos]: m/z=534 and 536 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.81-3.90 (m, 4H), 4.01 (dd, 1H), 4.24-4.34 (m, 1H), 5.29-5.40 (m, 2H), 6.89 (d, 1H), 7.42 (d, 1H), 7.64 (d, 2H), 7.69 (dd, 1H), 7.74 (d, 2H), 7.84 (d, 1H)。
Embodiment 105A
The bromo-2-of 4-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl) methyl benzoate
The compound and 818 mg (2.51 mmol) cesium carbonate that 515 mg (1.67 mmol) are derived from embodiment 5A are suspended in 10 ml acetonitriles, and add 810 mg (1.84 mmol) 4-bromo-2-(bromomethyl) methyl benzoate.Described mixture is stirred 3 h under reflux.After being cooled to room temperature, add 15 ml water, and with mixture described in each 10 ml extraction into ethyl acetate 3 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] Purification.Obtain 455 mg (51% of theoretical value) target compound.
LC/MS [method 4]: R t=1.21 min; MS [ESIpos]: m/z=534 and 536 (M+H) +.
Embodiment 106A
5-methyl-2'-(trifluoromethyl) biphenyl-2-methyl-formiate
Under argon, the bromo-methyl 4 methylbenzoate of 500 mg (2.18 mmol) 2-is dissolved in 10 ml toluene together with 655 mg (3.27 mmol) 2-(trifluoromethyl) phenyl-boron dihydroxide, and add successively 86 mg (0.22 mmol) 2-dicyclohexyl phosphino--2'-( n,N-dimethylamino) biphenyl, 100 mg (0.11 mmol) three (dibenzalacetone) two palladium and 927 mg (4.37 mmol) potassiumphosphate.Described mixture is heated to 110 DEG C, and stirs 20 h in this temperature.In order to carry out aftertreatment, described reaction mixture is cooled to room temperature, and dilutes with 20 ml ethyl acetate and 20 ml water.After being separated, also use each 20 ml extraction into ethyl acetate aqueous phase 2 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: first use cyclohexane/ethyl acetate 30:1, then uses 20:1) Purification.Obtain 597 mg (86% of theoretical value) target compound.
GC/MS [method 20]: R t=5.55 min; MS [EIpos]: m/z=294 (M) +.
Embodiment 107A
The chloro-5-methyl diphenyl of 2'--2-methyl-formiate
With the preparation of embodiment 107A similarly, react the 500 mg bromo-methyl 4 methylbenzoate of (2.18 mmol) 2-and 512 mg (3.27 mmol) 2-chlorophenylboronic acid.Obtain 275 mg (48% of theoretical value) target compound.
LC/MS [method 4]: R t=1.22 min; MS [ESIpos]: m/z=261 (M+H) +.
Embodiment 108A
5-(bromomethyl)-2'-(trifluoromethyl) biphenyl-2-methyl-formiate
590 mg (2.01 mmol) are derived from the compound of embodiment 107A, 357 mg (2.01 mmol) n-bromine succinimide and 33 mg (0.20 mmol) 2,2'-azo two-2-methyl propionitrile heat 16 h under reflux in 8 ml tetracol phenixin.After being cooled to room temperature, with mixture described in 10 ml dchloromethane, and with 10 ml water washings.Organic phase, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 346 mg (30% of theoretical value) target compound, purity be 64% its react further immediately.
LC/MS [method 4]: R t=1.27 min; MS [DCI]: m/z=390 and 392 (M+NH 4) +.
Embodiment 109A
5-(bromomethyl)-2'-chlordiphenyl-2-methyl-formiate
With the preparation of embodiment 109A similarly, the compound making 270 mg (1.04 mmol) derive from embodiment 108A with n-bromine succinimide reacts.Obtain 232 mg (66% of theoretical value) target compound, it reacts immediately further.
LC/MS [method 4]: R t=1.22 min; MS [DCI]: m/z=356 and 358 (M+NH 4) +.
Embodiment 110A
2'-chlordiphenyl-3,5-dicarboxylic acid dimethyl ester
Under argon, the different dimethyl isophthalate of 500 mg (1.83 mmol) 5-bromine is dissolved in 8 ml toluene together with 429 mg (2.75 mmol) 2-chlorophenylboronic acid, and add successively 72 mg (0.18 mmol) 2-dicyclohexyl phosphino--2'-( n,N-dimethylamino) biphenyl, 84 mg (0.09 mmol) three (dibenzalacetone) two palladium and 777 mg (3.66 mmol) potassiumphosphate.Described mixture is heated to 110 DEG C, and stirs 20 h in this temperature.In order to carry out aftertreatment, described reaction mixture is cooled to room temperature, and with 20 ml diluted ethyl acetate.Suction filtration solid, and with each 10 ml ethyl acetate debris 3 times.The filtrate merged with each 10 ml water washings 2 times.Organic phase, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] Purification.Obtain 305 mg (55% of theoretical value) target compound.
LC/MS [method 4]: R t=1.24 min; MS [EIpos]: m/z=305 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.92 (s, 6H), 7.46-7.55 (m, 3H), 7.60-7.68 (m, 1H), 8.23 (d, 2H), 8.52 (t, 1H)。
Embodiment 111A
The chloro-5-of 2'-(methylol) biphenyl-3-methyl-formiate
305 mg (1.00 mmol) are derived from the compound dissolution of embodiment 110A in 6 ml THF, and add the 1 M solution of 0.5 ml (0.50 mmol) lithium aluminum hydride in THF at-10 DEG C.Then by described reaction mixture at stirring at room temperature 1 h.In order to carry out aftertreatment, add the saturated aqueous sodium potassium tartrate of 3 ml in room temperature, and with mixture described in 15 ml extraction into ethyl acetate.Wash organic phase 1 time with the saturated potassium sodium tartrate solution of 10 ml, through dried over mgso, filter, and concentrate in a vacuum.By chromatography [method 19] Purification.Obtain 189 mg (68% of theoretical value) target compound.
LC/MS [method 4]: R t=1.03 min; MS [ESIpos]: m/z=277 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.88 (s, 3H), 4.63 (d, 2H), 5.43 (t, 1H), 7.43-7.47 (m, 3H), 7.58-7.62 (m, 1H), 7.62-7.64 (m, 1H), 7.84-7.87 (m, 1H), 7.97-8.00 (m, 1H)。
Embodiment 112A
5-(bromomethyl)-2'-chlordiphenyl-3-methyl-formiate
187 mg (0.68 mmol) are derived from the compound of embodiment 111A and 266 mg (1.01 mmol) triphenylphosphine dissolved in 6 ml THF, and add 336 mg (1.01 mmol) carbon tetrabromide in room temperature.Then by described mixture at stirring at room temperature 16 h.In order to carry out aftertreatment, with mixture described in 20 g diatomite filtrations, with ethyl acetate washing, and concentrated filtrate in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 7:3) Purification.Obtain 275 mg (>100% theoretical value) target compound, it reacts immediately further.
1H-NMR (400 MHz, DMSO-d 6): δ= 3.89 (s, 3H), 4.86 (s, 2H), 7.44-7.50 (m, 3H), 7.58-7.64 (m, 1H), 7.80-7.82 (m, 1H), 7.90-7.92 (m, 1H), 8.08-8.11 (m, 1H)。
Embodiment 113A and embodiment 114A
The bromo-2'-chlordiphenyl of 5--3-methyl-formiate
with
Chloro-1,1':3', the 1''-terphenyl-5'-methyl-formiate of 2,2''-bis-
Under argon, 60 mg (0.05 mmol) tetrakis triphenylphosphine palladium (0) are added in 300 mg (1.02 mmol) 3, the 5-methyl-dibromobenzoates in 6 ml dioxs.Described mixture is heated to 110 DEG C, and adds 1.0 ml (2.00 mmol) 2 M aqueous sodium carbonate successively and be dissolved in 239 mg (1.53 mmol) the 2-chlorophenylboronic acid in 1 ml diox.Then described mixture is stirred 1 h at 110 DEG C.In order to carry out aftertreatment, described reaction mixture is cooled to room temperature, and dilutes with 20 ml ethyl acetate and 20 ml water.After being separated, also use each 20 ml extraction into ethyl acetate aqueous phase 2 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By preparation HPLC [method 19], resistates is separated into various ingredients.Obtain 142 mg (43% of theoretical value) 5-bromo-2'-chlordiphenyl-3-methyl-formiate (embodiment 113A) and 166 mg (46% of theoretical value) 2,2''-bis-chloro-1,1':3', 1''-terphenyl-5'-methyl-formiate (embodiment 114A) is as reaction product.
embodiment 113A:
GC/MS [method 20]: R t=7.50 min; MS [ESIpos]: m/z=324 and 326 (M) +.
embodiment 114A:
GC/MS [method 20]: R t=10.26 min; MS [ESIpos]: m/z=356 and 358 (M) +.
Embodiment 115A
(the bromo-2'-chlordiphenyl of 5--3-base) methyl alcohol
170 mg (0.52 mmol) are derived from the compound dissolution of embodiment 113A in 6 ml THF, and add the 1 M solution of 0.37 ml (0.37 mmol) lithium aluminum hydride in THF at-10 DEG C.Then by described mixture at stirring at room temperature 1 h.In order to carry out aftertreatment, add the saturated aqueous sodium potassium tartrate of 4 ml in room temperature, and with mixture described in 15 ml extraction into ethyl acetate.Wash organic phase 1 time with the saturated potassium sodium tartrate solution of 10 ml, through dried over mgso, filter, and concentrate in a vacuum.Obtain 177 mg (>100% theoretical value) target compound.
LC/MS [method 2]: R t=2.39 min.
GC/MS [method 20]: R t=7.67 min; MS [ESIpos]: m/z=296 and 298 (M) +.
Embodiment 116A
(chloro-1,1':3', the 1''-terphenyl-5'-base of 2,2''-bis-) methyl alcohol
With the preparation of embodiment 115A similarly, react the compound that 311 mg (0.87 mmol) derive from embodiment 114A.Obtain 283 mg (91% of theoretical value) target compound.
LC/MS [method 2]: R t=2.63 min.
MS [DCI]: m/z = 346 (M+NH 4) +。
Embodiment 117A
The bromo-5'-of 3'-(bromomethyl)-2-chlordiphenyl
177 mg (0.60 mmol) are derived from the compound of embodiment 115A and 187 mg (0.71 mmol) triphenylphosphine dissolved in 4 ml THF, and add 237 mg (0.71 mmol) carbon tetrabromide in room temperature.Then by described mixture at stirring at room temperature 16 h.In order to carry out aftertreatment, with mixture described in 20 g diatomite filtrations, and concentrated filtrate in a vacuum.By chromatography [method 19] Purification.Obtain 129 mg (60% of the theoretical value) target compound that purity is 79%, it reacts immediately further.
LC/MS [method 4]: R t=1.41 min.
Embodiment 118A
Chloro-1,1':3', the 1''-terphenyl of 5'-(bromomethyl)-2,2''-bis-
With the preparation of embodiment 117A similarly, react the compound that 280 mg (0.85 mmol) derive from embodiment 116A.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 10:1), purification of crude product.Obtain 300 mg (76% of theoretical value) target compound.
GC/MS [method 20]: R t=10.64 min; MS [ESIpos]: m/z=390,392 and 394 (M) +
MS [DCI]: m/z=408,410 and 412 (M+NH 4) +.
Embodiment 119A
2-[(3-bromophenyl) alkylsulfonyl]-5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
360 mg (1.17 mmol) are derived from the compound dissolution of embodiment 5A in 10 ml THF, and at 0 DEG C, add 94 mg (2.34 mmol) sodium hydride (dispersed system of in mineral oil 60%).After 20 min, add 299 mg (1.17 mmol) 3-bromobenzene sulfonyl chloride, and described mixture is stirred 1 h at 0 DEG C.In order to carry out aftertreatment, 10 ml water are added in this mixture, and with mixture described in each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 8:1, then 1:1) purification of crude product.Obtain 181 mg (27% of theoretical value) target compound.
LC/MS [method 3]: R t=1.33 min; MS [ESIpos]: m/z=526 and 528 (M+H) +.
Embodiment 120A
2-[(3-bromophenyl) alkylsulfonyl]-5-(4-chloro-phenyl-)-4-[(1 e)-3,3,3-trifluoropropyl-1-alkene-1-bases]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
500 mg (1.63 mmol) are derived from the compound dissolution of embodiment 5A in 10 ml acetonitriles, and add 449 mg (3.25 mmol) salt of wormwood and 415 mg (1.63 mmol) 3-bromobenzene sulfonyl chloride.Described mixture is heated 2 h under reflux.In order to carry out aftertreatment, 10 ml water are added in this mixture, and with mixture described in each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 8:1 → 5:1 → 1:1) purification of crude product.Obtain 285 mg (34% of theoretical value) target compound.
LC/MS [method 4]: R t=1.31 min; MS [ESIpos]: m/z=508 and 510 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 6.72 (dq, 1H), 6.89-6.95 (m, 1H), 7.62-7.66 (m, 2H), 7.67-7.73 (m, 3H), 8.05-8.11 (m, 2H), 8.14 (t, 1H)。
Embodiment 121A
5-(4-chloro-phenyl-)-4-cyclopropyl-2-(methylol)-2,4-dihydro-3 h-1,2,4-triazole-3-ketone
By 7 ml formaldehyde in water 37% solution add 1000 mg (4.24 mmol) 5-(4-chloro-phenyl-)-4-cyclopropyl-2,4-dihydro-3 hin-1,2,4-triazole-3-ketone [preparing according to WO 2007/134862 embodiment 36A], and by described mixture at stirring at room temperature 20 h.The solid of suction filtration precipitation, and wash with water.Dry under a high vacuum, obtain 878 mg (62% of theoretical value) target compound.
1H-NMR (400 MHz, CDCl 3): δ= 0.71-0.78 (m, 2H), 0.98-1.06 (m, 2H), 2.98 (m, 1H), 5.34 (s, 2H), 7.46 (d, 2H), 7.69 (d, 2H)。
Embodiment 122A
2-(chloromethyl)-5-(4-chloro-phenyl-)-4-cyclopropyl-2,4-dihydro-3 h-1,2,4-triazole-3-ketone
The compound that 875 mg (3.29 mmol) derive from embodiment 121A is suspended in 3 ml methylene dichloride, and adds a DMF and 288 μ l (3.95 mmol) thionyl chloride.By described mixture at stirring at room temperature 3 h.In order to carry out aftertreatment, add 5 ml saturated sodium bicarbonate aqueous solutions.Described mixture 1 time is extracted by 10 ml t-butyl methyl ether.By 5 ml water washing organic phase 1 time, through dried over sodium sulfate, filter, and concentrate in a vacuum.Under a high vacuum after dried residue, obtain 803 mg (86% of theoretical value) target compound.
1H-NMR (400 MHz, CDCl 3): δ= 0.74-0.80 (m, 2H), 1.00-1.06 (m, 2H), 2.98 (m, 1H), 5.66 (s, 2H), 7.48 (d, 2H), 7.72 (d, 2H)。
Working Examples:
Embodiment 1
5-(5-chlorothiophene-2-base)-4-(2-luorobenzyl)-2-({ 3-[2-(trifluoromethyl) phenyl]-1,2,4-oxadiazole-5-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
Under argon, 95 mg (0.18 mmol) benzotriazole-1-base oxygen base-three (pyrrolidyl) phosphorus hexafluorophosphate is added 56 mg (0.15 mmol) [3-(the chloro-2-thienyl of 5-)-4-(2-luorobenzyl)-5-oxo-4,5-dihydro-1 h-1,2,4-triazol-1-yl] acetic acid [preparing according to WO 2007/134862 embodiment 154A] and 32 μ l (0.18 mmol) n,Nin the solution of-diisopropylethylamine in the DMF of 1.5 ml dryings.After stirring 20 min, add 34 mg (0.17 mmol) n'-hydroxyl-2-(trifluoromethyl) benzenyl amidine.Then by described mixture at stirring at room temperature 16 h.In order to carry out aftertreatment, 10 ml water are added in this mixture, and with mixture described in each 10 ml extraction into ethyl acetate 3 times.By the organic phase that water and the saturated common salt solution washing of each 10 ml merge, filtered by Extrelut, and concentrate in a vacuum.Resistates is dissolved in 2 ml DMF, and at 250 DEG C, stirs 15 min in microwave oven.After cooling, on the rotary evaporator under reduced pressure except desolventizing, and at the upper chromatographic separation crude product of silica gel (elutriant: cyclohexane/ethyl acetate 4:1).Obtaining 60 mg (72% of theoretical value) target compound like this, is yellow coloured resin.
LC/MS [method 9]: R t=4.25 min; MS [ESIpos]: m/z=536 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 5.15 (s, 2H), 5.42 (s, 2H), 6.35 (d, 2H), 6.93 (d, 2H), 7.01-7.29 (m, 3H), 7.23-7.34 (m, 1H), 7.60-7.70 (m, 2H), 7.76-7.89 (m, 2H)。
Embodiment 2
2-{ [3-(2-chlorobenzyl)-1,2,4-oxadiazole-5-base] methyl }-5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
50 mg (0.13 mmol) are derived from the compound dissolution of embodiment 7A in 2 ml toluene, add 51 mg (0.28 mmol) (1 z)-2-(2-chloro-phenyl-)- n'-hydroxyl acetamidine and 38 mg (0.28 mmol) salt of wormwood, and described mixture is heated 6 h under reflux.In order to carry out aftertreatment, 10 ml water are added in this mixture, and with mixture described in each 10 ml extraction into ethyl acetate 2 times.The organic phase merged with 10 ml water and the washing of 10 ml saturated nacl aqueous solutions 1 time, through dried over sodium sulfate, filters, and concentrates in a vacuum.By chromatography [method 19] purification of crude product.Obtain 40 mg (59% of theoretical value) target compound.
LC/MS [method 4]: R t=1.19 min; MS [ESIpos]: m/z=514 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.97 (dd, 1H), 4.04 (dd, 1H), 4.22 (s, 2H), 4.47-4.59 (m, 1H), 4.64 (br. s, 1H), 5.25 (d, 1H), 5.32 (d, 1H), 7.19-7.29 (m, 3H), 7.35-7.42 (m, 1H), 7.46-7.51 (m, 2H), 7.54-7.60 (m, 2H)。
Embodiment 3
5-(4-chloro-phenyl-)-2-{ [3-(2-methyl-benzyl)-1,2,4-oxadiazole-5-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of compound in example 2 similarly, the compound being derived from embodiment 7A by 50 mg (0.13 mmol) obtains 45 mg (69% of theoretical value) title compound.
LC/MS [method 3]: R t=1.38 min; MS [ESIpos]: m/z=494 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 2.33 (s, 3H), 3.97 (dd, 1H), 4.01-4.08 (m, 3H), 4.44 (d, 1H), 4.47-4.54 (m, 1H), 5.23 (d, 1H), 5.30 (d, 1H), 7.13-7.22 (m, 4H), 7.49 (d, 2H), 7.55 (d, 2H)。
Embodiment 4
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 3-[3-(trifluoromethyl) benzyl]-1,2,4-oxadiazole-5-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of compound in example 2 similarly, the compound being derived from embodiment 7A by 50 mg (0.13 mmol) obtains 24 mg (34% of theoretical value) title compound.
LC/MS [method 3]: R t=1.43 min; MS [ESIpos]: m/z=548 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.99 (dd, 1H), 4.06 (dd, 1H), 4.14 (s, 2H), 4.45-4.57 (m, 2H), 5.23-5.34 (m, 2H), 7.41-7.60 (m, 8H)。
Embodiment 5
5-(4-chloro-phenyl-)-2-{ [3-(2-aminomethyl phenyl)-1,2,4-oxadiazole-5-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of compound in example 2 similarly, derive from the compound of embodiment 7A after the reaction times of 20 h by 50 mg (0.13 mmol), obtain 47 mg (74% of theoretical value) title compound.
LC/MS [method 4]: R t=1.22 min; MS [ESIpos]: m/z=480 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 2.60 (s, 3H), 3.98-4.06 (m, 1H), 4.06-4.12 (m, 1H), 4.50 (d, 1H), 4.56 (d, 1H), 5.34-5.44 (m, 2H), 7.31 (d, 2H), 7.36-7.42 (m, 1H), 7.47-7.53 (m, 2H), 7.55-7.61 (m, 2H), 7.94 (d, 1H)。
Embodiment 6
5-(4-chloro-phenyl-)-2-{ [3-(2-chloro-phenyl-)-1,2,4-oxadiazole-5-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of compound in example 2 similarly, derive from the compound of embodiment 7A after the reaction times of 20 h by 50 mg (0.13 mmol), obtain 52 mg (79% of theoretical value) title compound.
LC/MS [method 4]: R t=1.17 min; MS [ESIpos]: m/z=500 and 502 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.95-4.15 (m, 2H), 4.51-4.62 (m, 1H), 5.33-5.48 (m, 2H), 7.34-7.56 (m, 5H), 7.56-7.64 (m, 2H), 7.89 (d, 1H)。
Embodiment 7
5-(4-chloro-phenyl-)-2-{ [3-(2,6-difluorophenyl)-1,2,4-oxadiazole-5-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of compound in example 2 similarly, derive from the compound of embodiment 7A after the reaction times of 2 h by 50 mg (0.13 mmol), obtain 46 mg (70% of theoretical value) title compound.
LC/MS [method 4]: R t=1.13 min; MS [ESIpos]: m/z=502 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.99 (dd, 1H), 4.08 (dd, 1H), 4.53-4.62 (m, 1H), 4.66 (d, 1H), 5.36-5.49 (m, 2H), 7.01-7.10 (m, 2H), 7.44-7.54 (m, 3H), 7.58-7.64 (m, 2H)。
Embodiment 8
5-(4-chloro-phenyl-)-2-{ [3-(2,3-difluorophenyl)-1,2,4-oxadiazole-5-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of compound in example 2 similarly, derive from the compound of embodiment 7A after the reaction times of 2 h by 50 mg (0.13 mmol), obtain 47 mg (71% of theoretical value) title compound.
LC/MS [method 4]: R t=1.18 min; MS [ESIpos]: m/z=502 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 4.03 (dd, 1H), 4.07-4.13 (m, 1H), 4.38 (d, 1H), 4.52-4.59 (m, 1H), 5.35-5.47 (m, 2H), 7.17-7.25 (m, 1H), 7.34 (q, 1H), 7.51 (d, 2H), 7.58 (d, 2H), 7.79 (t, 1H)。
Embodiment 9
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 3-[2-(trifluoromethyl) phenyl]-1,2,4-oxadiazole-5-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of compound in example 2 similarly, the compound being derived from embodiment 7A by 50 mg (0.13 mmol) obtains 50 mg (71% of theoretical value) title compound.
LC/MS [method 3]: R t=1.39 min; MS [ESIpos]: m/z=534 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 4.01 (dd, 1H), 4.08 (dd, 1H), 4.47-4.51 (m, 1H), 4.52-4.61 (m, 1H), 5.36-5.47 (m, 2H), 7.50 (d, 2H), 7.59 (d, 2H), 7.63-7.69 (m, 2H), 7.76-7.87 (m, 2H)。
Embodiment 10
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 3-[3-(trifluoromethyl) phenyl]-1,2,4-oxadiazole-5-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of compound in example 2 similarly, derive from the compound of embodiment 7A after the reaction times of 2 h by 50 mg (0.13 mmol), obtain 44 mg (62% of theoretical value) title compound.
LC/MS [method 4]: R t=1.25 min; MS [ESIpos]: m/z=534 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 4.05 (dd, 1H), 4.08-4.14 (m, 1H), 4.37 (d, 1H), 4.52-4.58 (m, 1H), 5.35-5.45 (m, 2H), 7.50 (d, 2H), 7.56-7.61 (m, 2H), 7.63 (d, 1H), 7.77 (d, 1H), 8.26 (d, 1H), 8.34 (s, 1H)。
Embodiment 11
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 3-[3-(trifluoromethoxy) phenyl]-1,2,4-oxadiazole-5-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of compound in example 2 similarly, derive from the compound of embodiment 7A after the reaction times of 2 h by 50 mg (0.13 mmol), obtain 53 mg (73% of theoretical value) title compound.
LC/MS [method 4]: R t=1.27 min; MS [ESIpos]: m/z=550 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 4.04 (dd, 1H), 4.08-4.12 (m, 1H), 4.47 (d, 1H), 4.52-4.59 (m, 1H), 5.34-5.44 (m, 2H), 7.37 (d, 1H), 7.46-7.55 (m, 3H), 7.56-7.61 (m, 2H), 7.93 (s, 1H), 8.01 (d, 1H)。
Embodiment 12
5-(4-chloro-phenyl-)-2-{ [3-(2,3-dichlorophenyl)-1,2,4-oxadiazole-5-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of compound in example 2 similarly, derive from the compound of embodiment 7A after the reaction times of 20 h by 50 mg (0.13 mmol), obtain 51 mg (72% of theoretical value) title compound.
LC/MS [method 4]: R t=1.26 min; MS [ESIpos]: m/z=534 and 536 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.86 (dd, 1H), 3.99-4.06 (m, 1H), 4.26-4.32 (m, 1H), 5.58 (s, 2H), 6.94 (d, 1H), 7.57 (t, 1H), 7.65 (d, 2H), 7.78 (d, 2H), 7.86 (d, 1H), 7.91 (d, 1H)。
Embodiment 13
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 3-[2-(trifluoromethoxy) phenyl]-1,2,4-oxadiazole-5-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of compound in example 2 similarly, derive from the compound of embodiment 7A after the reaction times of 20 h by 50 mg (0.13 mmol), obtain 37 mg (52% of theoretical value) title compound.
LC/MS [method 4]: R t=1.25 min; MS [ESIpos]: m/z=550 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.87 (dd, 1H), 4.02 (dd, 1H), 4.25-4.34 (m, 1H), 5.57 (s, 2H), 6.94 (d, 1H), 7.60-7.67 (m, 4H), 7.73-7.80 (m, 3H), 8.09 (dd, 1H)。
Embodiment 14
5-(5-chlorothiophene-2-base)-4-(2-luorobenzyl)-2-({ 5-[3-(trifluoromethyl) benzyl]-1,2,4-oxadiazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
Under argon, 81 mg (0.16 mmol) benzotriazole-1-base oxygen base-three (pyrrolidyl) phosphorus hexafluorophosphate is added 29 mg (0.14 mmol) 3-(trifluoromethyl) toluylic acid and 27 μ l (0.16 mmol) n,Nin the solution of-diisopropylethylamine in the DMF of 1.3 ml dryings.After stirring 30 min, add the compound that 50 mg (0.13 mmol) derive from embodiment 25A, and by described mixture at stirring at room temperature 18 h.Then 2 ml water are added, and with mixture described in each 5 ml extraction into ethyl acetate 3 times.By the organic phase that water and the sodium chloride solution washing of each 5 ml merge, filtered by Extrelut, and under reduced pressure concentrate.Resistates is dissolved in 2 ml DMF, and stirs 15 min at 250 DEG C in microwave oven.After cooling, on the rotary evaporator under reduced pressure except desolventizing, and by chromatography [method 15] purification of crude product.Obtaining 25 mg (34% of theoretical value) target compound like this, is deep yellow resin.
LC/MS [method 9]: R t=4.28 min; MS [ESIpos]: m/z=550 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 5.12 (s, 2H), 5.20 (s, 2H), 6.32 (d, 2H), 6.90 (d, 2H), 7.04-7.19 (m, 3H), 7.22-7.34 (m, 1H), 7.43-7.55 (m, 2H), 7.55-7.62 (m, 2H)。
Embodiment 15
5-(5-chlorothiophene-2-base)-4-(2-luorobenzyl)-2-({ 5-[2-(trifluoromethyl) phenyl]-1,2,4-oxadiazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 14 similarly, the compound being derived from embodiment 25A by 50 mg (0.13 mmol) obtains 35 mg (49% of theoretical value) title compound.
MS [ESIpos]: m/z = 536 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 5.16 (s, 2H), 5.35 (s, 2H), 6.33 (d, 2H), 6.92 (d, 2H), 7.04-7.13 (m, 2H), 7.13-7.20 (m, 1H), 7.23-7.33 (m, 1H), 7.68-7.78 (m, 2H), 7.83-7.92 (m, 1H), 7.96-8.05 (m, 1H)。
Embodiment 16
5-(5-chlorothiophene-2-base)-4-(2-luorobenzyl)-2-({ 5-[2-(trifluoromethyl) benzyl]-1,2,4-oxadiazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 14 similarly, the compound being derived from embodiment 25A by 50 mg (0.13 mmol) obtains 15 mg (20% of theoretical value) title compound.
MS [CIpos]: m/z = 550 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 4.93 (s, 2H), 5.14 (s, 2H), 5.20 (s, 2H), 6.82 (d, 2H), 6.90 (d, 2H), 7.04-7.18 (m, 3H), 7.25-7.35 (m, 1H), 7.35-7.50 (m, 2H), 7.50-7.59 (m, 1H), 7.66-7.75 (m, 1H)。
Embodiment 17
5-(4-chloro-phenyl-)-2-{ [5-(2-chloro-phenyl-)-1,3,4-oxadiazole-2-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
85 mg (0.28 mmol) are derived from the compound dissolution of embodiment 5A in 5 ml acetonitriles, and add 180 mg (0.55 mmol) cesium carbonate and 66 mg (0.29 mmol) 2-(chloromethyl)-5-(2-chloro-phenyl-)-1,3,4-oxadiazole.Described mixture is stirred 1 h at 80 DEG C.In order to carry out aftertreatment, described mixture is cooled to room temperature, and adds 10 ml water.With mixture described in each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 66 mg (48% of theoretical value) target compound.
LC/MS [method 4]: R t=1.12 min; MS [ESIpos]: m/z=500 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.85 (dd, 1H), 4.01 (dd, 1H), 4.25-4.31 (m, 1H), 5.41-5.51 (m, 2H), 6.90 (d, 1H), 7.55-7.60 (m, 1H), 7.61-7.69 (m, 3H), 7.70-7.78 (m, 3H), 7.94 (dd, 1H)。
Embodiment 18
5-(4-chloro-phenyl-)-2-{ [5-(2-chloro-phenyl-)-1,3,4-thiadiazoles-2-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
30 mg (0.10 mmol) are derived from the compound dissolution of embodiment 5A in 3 ml acetonitriles, and add the compound that 48 mg (0.15 mmol) cesium carbonate and 28 mg (0.10 mmol) derive from embodiment 86A.Described mixture is stirred 8 h at 70 DEG C.In order to carry out aftertreatment, described mixture being cooled to room temperature, with 5 ml methanol dilution, and filtering.Concentrated filtrate in a vacuum, then by chromatography [method 19] purification of crude product.Obtain 11 mg (22% of theoretical value) target compound.
LC/MS [method 6]: R t=2.48 min; MS [ESIpos]: m/z=516 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.85 (dd, 1H), 4.01 (dd, 1H), 4.24-4.35 (m, 1H), 5.56-5.65 (m, 2H), 6.92 (s, 1H), 7.53-7.59 (m, 1H), 7.59-7.67 (m, 3H), 7.72 (dd, 1H), 7.77 (d, 2H), 8.14 (dd, 1H)。
Embodiment 19
5-(4-chloro-phenyl-)-2-{ [5-(2,3-dichlorophenyl)-1,3,4-thiadiazoles-2-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of embodiment 18 similarly, 36 mg (0.12 mmol) are derived from, and compound that the compound of embodiment 5A and 38 mg (0.12 mmol) derive from embodiment 87A reacts.Obtain 33 mg (48% of theoretical value) target compound.
LC/MS [method 4]: R t=1.25 min; MS [ESIpos]: m/z=550 and 552 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.85 (dd, 1H), 4.01 (dd, 1H), 4.25-4.35 (m, 1H), 5.56-5.66 (m, 2H), 6.94 (br. s, 1H), 7.57 (t, 1H), 7.64 (d, 2H), 7.78 (d, 2H), 7.90 (dd, 1H), 8.05 (dd, 1H)。
Embodiment 20
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 5-[2-(trifluoromethyl) phenyl]-1,3,4-thiadiazoles-2-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of embodiment 18 similarly, 33 mg (0.11 mmol) are derived from, and compound that the compound of embodiment 5A and 35 mg (0.11 mmol) derive from embodiment 85A reacts.Obtain 16 mg (27% of theoretical value) target compound.
LC/MS [method 3]: R t=1.33 min; MS [ESIpos]: m/z=550 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.86 (dd, 1H), 4.02 (dd, 1H), 4.25-4.35 (m, 1H), 5.56-5.65 (m, 2H), 6.92 (br. s, 1H), 7.62-7.67 (m, 2H), 7.75-7.88 (m, 5H), 7.97-8.01 (m, 1H)。
Embodiment 21
5-(4-chloro-phenyl-)-4-cyclopropyl-2-({ 5-[3-(trifluoromethyl) phenyl]-4 h-1,2,4-triazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
100 mg (0.33 mmol) are derived from the compound dissolution of embodiment 21A in 1.6 ml DMF, add 109 mg (0.49 mmol) 3-trifluoromethyl benzenyl amidine-hydrogenchloride, and described mixture is stirred 45 min at 150 DEG C in microwave oven.After cooling, under reduced pressure concentration response material on the rotary evaporator, and by the remaining resistates of chromatography [method 19] purifying.Obtaining 70 mg (47% of theoretical value) target compound, is colorless solid.
LC/MS [method 7]: R t=2.33 min; MS [ESIpos]: m/z=461 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.74-0.84 (m, 2H), 0.99-1.10 (m, 2H), 2.96-3.06 (m, 1H), 5.28 (s, 2H), 7.45 (d, 2H), 7.53 (t, 1H), 7.64 (d, 1H), 7.68 (d, 2H), 8.25 (d, 1H), 8.36 (s, 1H)。
Embodiment 22
5-(4-chloro-phenyl-)-4-cyclopropyl-2-({ 5-[2-(trifluoromethyl) benzyl]-4 h-1,2,4-triazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 21 similarly, the compound being derived from embodiment 21A by 100 mg (0.33 mmol) obtains 54 mg (35% of theoretical value) title compound.
MS [ESIpos]: m/z = 475 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.70-0.80 (m, 2H), 0.96-1.06 (m, 2H), 2.92-3.03 (m, 1H), 4.30 (s, 2H), 5.15 (s, 2H), 7.30-7.40 (m, 2H), 7.40-7.51 (m, 3H), 7.61-7.71 (m, 3H), 10.80 (br. s, 1H)。
Embodiment 23
5-(4-chloro-phenyl-)-4-cyclopropyl-2-({ 5-[3-(trifluoromethyl) benzyl]-4 h-1,2,4-triazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 21 similarly, the compound being derived from embodiment 21A by 75 mg (0.24 mmol) obtains 55 mg (48% of theoretical value) title compound.
LC/MS [method 5]: R t=2.42 min; MS [ESIpos]: m/z=475 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.70-0.79 (m, 2H), 0.96-1.06 (m, 2H), 2.93-3.03 (m, 1H), 4.14 (s, 2H), 5.15 (s, 2H), 7.38-7.51 (m, 5H), 7.56 (s, 1H), 7.62-7.70 (m, 2H)。
Embodiment 24
5-(4-chloro-phenyl-)-4-cyclopropyl-2-{ [5-(2,6-dichloro benzyl)-4 h-1,2,4-triazole-3-base] methyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
By 58 mg (0.24 mmol) 2-(2,6-dichlorophenyl) ethanamidine-hydrogenchloride puts into the methyl alcohol of 1 ml drying in advance, add the methanol solution of sodium methylate of 66 μ l (0.24 mmol) 25%, and by described mixture at stirring at room temperature 1 h.Then the compound that 50 mg (0.16 mmol) be dissolved in 0.6 ml methyl alcohol derive from embodiment 21A is added.By described reaction mass in stirred overnight at room temperature.The colorless solid of suction filtration precipitation, uses a small amount of methanol wash, and dry under a high vacuum.Then by described solid suspension in dimethylbenzene, and stir 4 h under reflux.After cooling, mixture described in evaporation concentration in a vacuum, and by chromatography [method 19] Purification.Obtaining 30 mg (39% of theoretical value) target compound, is colorless solid.
LC/MS [method 5]: R t=2.38 min; MS [ESIpos]: m/z=476 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.70-0.80 (m, 2H), 0.96-1.06 (m, 2H), 2.93-3.04 (m, 1H), 4.46 (s, 2H), 5.13 (s, 2H), 7.19 (t, 1H), 7.35 (d, 2H), 7.44 (d, 2H), 7.67 (d, 2H), 11.00 (br. s, 1H)。
Embodiment 25
5-(5-chlorothiophene-2-base)-4-(2-luorobenzyl)-2-({ 5-[3-(trifluoromethyl) phenyl]-4 h-1,2,4-triazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
100 mg (0.26 mmol) are derived from the compound dissolution of embodiment 22A in 1.0 ml DMF, add 88 mg (0.39 mmol) 3-(trifluoromethyl) benzenyl amidine-hydrogenchloride, and described mixture is stirred 30 min at 220 DEG C in microwave oven.After cooling, under reduced pressure concentration response material on the rotary evaporator, and by chromatography [method 19] Purification.Obtaining 71 mg (51% of theoretical value) target compound, is colourless resin.
MS [ESIpos]: m/z = 535 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 5.14 (s, 2H), 5.34 (s, 2H), 6.85 (s, 1H), 6.95 (s, 1H), 7.04-7.16 (m, 3H), 7.28-7.37 (m, 1H), 7.50-7.60 (m, 1H), 7.61-7.70 (m, 1H), 8.20-8.30 (m, 1H), 8.35 (s, 1H), 12.00 (br. s, 1H)。
Embodiment 26
5-(5-chlorothiophene-2-base)-4-(2-luorobenzyl)-2-({ 5-[2-(trifluoromethyl) benzyl]-4 h-1,2,4-triazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 25 similarly, the compound being derived from embodiment 22A by 75 mg (0.20 mmol) obtains 19 mg (18% of theoretical value) title compound.
LC/MS [method 5]: R t=2.62 min; MS [ESIpos]: m/z=549 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 4.32 (s, 2H), 5.11 (s, 2H), 5.21 (s, 2H), 6.82 (d, 1H), 6.90 (d, 1H), 7.03-7.16 (m, 3H), 7.25-7.32 (m, 1H), 7.32-7.44 (m, 2H), 7.45-7.52 (m, 1H), 7.68 (d, 1H), 10.70 (br. s, 1H)。
Embodiment 27
5-(5-chlorothiophene-2-base)-4-(2-luorobenzyl)-2-({ 5-[3-(trifluoromethyl) benzyl]-4 h-1,2,4-triazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 25 similarly, the compound being derived from embodiment 22A by 75 mg (0.20 mmol) obtains 29 mg (27% of theoretical value) title compound.
MS [ESIpos]: m/z = 549 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 4.15 (s, 2H), 5.11 (s, 2H), 5.22 (s, 2H), 6.84 (d, 1H), 6.91 (d, 1H), 7.03-7.15 (m, 3H), 7.25-7.34 (m, 1H), 7.44 (d, 1H), 7.48-7.53 (m, 2H), 7.58 (s, 1H), 11.10 (br. s, 1H)。
Embodiment 28
3-{ [3-(4-chloro-phenyl-)-5-oxo-1-({ 5-[2-(trifluoromethyl) benzyl]-4 h-1,2,4-triazole-3-base } methyl)-1,5-dihydro-4 h-1,2,4-triazole-4-yl] methyl } methyl benzoate
77 mg (0.27 mmol) 2-[2-(trifluoromethyl) phenyl] ethanamidine-hydrogen bromide is dissolved in the methyl alcohol of 1 ml drying, add the methanol solution of sodium methylate of 74 μ l (0.27 mmol) 25%, and stir 30 min.Then add the compound that 75 mg (0.18 mmol) derive from embodiment 16A, and first at stirring at room temperature 16 h, then stir 5 h under reflux.Then by chromatography [method 19] directly mixture described in purifying.Obtaining 67 mg (64% of theoretical value) target compound, is colourless foam.
LC/MS [method 5]: R t=2.59 min; MS [ESIpos]: m/z=583 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.88 (s, 3H), 4.31 (s, 2H), 5.00 (s, 2H), 5.25 (s, 2H), 7.29-7.44 (m, 8H), 7.49 (d, 1H), 7.58 (d, 1H), 7.90 (s, 1H), 7.95 (d, 1H)。
Embodiment 29
3-{ [3-(4-chloro-phenyl-)-1-{ [5-(2,6-dichloro benzyl)-4 h-1,2,4-triazole-3-base] methyl }-5-oxo-1,5-dihydro-4 h-1,2,4-triazole-4-yl] methyl } methyl benzoate
With the preparation of the compound in embodiment 28 similarly, the compound being derived from embodiment 16A by 80 mg (0.19 mmol) produces 67 mg (60% of theoretical value) title compound.
MS [ESIpos]: m/z=583 and 585 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.90 (s, 3H), 4.49 (s, 2H), 5.00 (s, 2H), 5.24 (s, 2H), 7.19 (t, 1H), 7.28-7.44 (m, 8H), 7.88-8.00 (m, 2H), 11.20 (br. s, 1H)。
Embodiment 30
5-(4-chloro-phenyl-)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2-({ 5-[2-(trifluoromethyl) benzyl]-4 h-1,2,4-triazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
370 mg (0.97 mmol) are derived from the compound dissolution of embodiment 18A in 5 ml DMF, add 349 mg (1.46 mmol) 2-[2-(trifluoromethyl) phenyl] ethanamidine-hydrogenchloride, and described mixture is stirred 90 min at 200 DEG C in microwave oven.After cooling, with reactant described in 5 ml methanol dilution, and by chromatography [method 19] direct purification.Obtain 170 mg (32% of theoretical value) target compound.
LC/MS [method 3]: R t=1.24 min; MS [ESIpos]: m/z=547 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.87-4.00 (m, 2H), 4.21 (s, 2H), 4.56-4.62 (m, 1H), 5.03-5.21 (m, 2H), 5.70 (br. s, 1H), 7.31 (d, 1H), 7.38 (t, 1H), 7.44 (d, 2H), 7.49 (t, 1H), 7.59 (s, 2H), 7.67 (d, 1H), 11.48 (br. s, 1H)。
Embodiment 31
3-{ [3-(4-chloro-phenyl-)-5-oxo-1-({ 5-[2-(trifluoromethyl) benzyl]-4 h-1,2,4-triazole-3-base } methyl)-1,5-dihydro-4 h-1,2,4-triazole-4-yl] methyl } phenylformic acid
The compound that 62 mg (0.11 mmol) derive from embodiment 28 is suspended in 1 ml ethanol, and adds 213 μ l (0.21 mmol) 1 M aqueous sodium hydroxide solution.Described mixture is stirred 4 h at 50 DEG C.After being cooled to room temperature, with in 215 μ l 1 M hydrochloric acid and described reactant, concentrate in a vacuum, and by chromatography [method 19] Purification.Obtaining 37 mg (61% of theoretical value) target compound, is colourless foam.
MS [ESIpos]: m/z = 569 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 4.04-4.35 (m, 2H), 4.90-5.25 (m, 4H), 7.25-7.38 (m, 1H), 7.38-7.54 (m, 7H), 7.54-7.65 (m, 1H), 7.65-7.78 (m, 2H), 7.80 (d, 1H), 13.02 (br. s, 1H), 13.65-13.93 (br. s, 1H)。
Embodiment 32
3-{ [3-(4-chloro-phenyl-)-1-{ [5-(2,6-dichloro benzyl)-4 h-1,2,4-triazole-3-base] methyl }-5-oxo-1,5-dihydro-4 h-1,2,4-triazole-4-yl] methyl } phenylformic acid
With the preparation of the compound in embodiment 31 similarly, the compound being derived from embodiment 29 by 60 mg (0.10 mmol) obtains 40 mg (68% of theoretical value) title compound.
MS [ESIpos]: m/z = 569 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 4.16-4.44 (m, 2H), 4.85-5.25 (m, 4H), 7.24-7.40 (m, 2H), 7.43 (t, 1H), 7.45-7.58 (m, 6H), 7.70 (s, 1H), 7.82 (d, 1H), 13.03 (br. s, 1H), 13.70 (br. s, 1H)。
Embodiment 33
5-(4-chloro-phenyl-)-4-cyclopropyl-2-[(5-{2-[3-(trifluoromethyl) phenyl] propane-2-base }-4 h-1,2,4-triazole-3-base) methyl]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
42 mg (0.14 mmol) are derived from the compound dissolution of embodiment 21A in 1.2 ml DMF, add 40 mg (0.15 mmol) 2-methyl-2-[3-(trifluoromethyl) phenyl] the third amidine-hydrogenchloride and 9 mg (0.16 mmol) sodium methylate, and described mixture is stirred 2 h at 180 DEG C in microwave reactor.After being cooled to room temperature, by preparation HPLC [method 19] directly mixture described in purifying.Obtaining 2 mg (3% of theoretical value) target compound, is colourless foam.
LC/MS [method 1]: R t=2.06 min; MS [ESIpos]: m/z=503 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.75-0.79 (m, 2H), 1.00-1.05 (m, 2H), 1.79 (s, 6H), 2.96-3.02 (m, 1H), 5.16 (s, 2H), 7.38-7.43 (q, 1H), 7.45 (d, 2H), 7.46-7.49 (m, 2H), 7.59 (s, 1H), 7.67 (d, 2H)。
Embodiment 34
5-(4-chloro-phenyl-)-4-cyclopropyl-2-({ 5-[1-(2-fluorophenyl)-1-methylethyl]-4 h-1,2,4-triazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
60 mg (0.20 mmol) are derived from the compound dissolution of embodiment 21A in 1 ml DMF, and add 63 mg (0.29 mmol) 2-(2-fluorophenyl)-2-methyl-prop amidine-hydrogenchloride and 17 mg (0.31 mmol) sodium methylate.Described suspension is stirred 8 h at 150 DEG C.Subsequently, by stirring 45 min at 200 DEG C in microwave reactor, make to react completely.With suspension described in about 1 ml methanol dilution, filter, and by preparation HPLC [method 19] purifying filtrate.Obtain 13 mg (15% of theoretical value) title compound.
LC/MS [method 5]: R t=2.30 min; MS [ESIpos]: m/z=453 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.75 (m, 2H), 0.95 (m, 2H), 1.88 (s, 6H), 2.99 (m, 1H), 5.32 (s, 2H), 6.93-7.00 (m, 1H), 7.14-7.21 (m, 1H), 7.38-7.49 (m, 4H), 7.62-7.72 (m, 2H)。
Embodiment 35
5-(4-chloro-phenyl-)-4-cyclopropyl-2-[(5-{2-[3-(trifluoromethyl) phenyl] ethyl }-4 h-1,2,4-triazole-3-base) methyl]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
50 mg (0.16 mmol) are derived from the compound dissolution of embodiment 21A in 1 ml DMF, add 62 mg (0.24 mmol) 3-[3-(trifluoromethyl) phenyl] the third amidine-hydrogenchloride, and described mixture is stirred 1 h at 180 DEG C in microwave oven.After cooling, with reaction mixture described in methanol dilution, and be directly separated described solution by preparation HPLC [method 19].Obtain 11 mg (14% of theoretical value) title compound.
LC/MS [method 1]: R t=1.96 min; MS [ESIpos]: m/z=489 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.71-0.81 (m, 2H), 0.98-1.06 (m, 2H), 2.99 (m, 1H), 3.03-3.09 (m, 2H), 3.10-3.16 (m, 2H), 5.16 (s, 2H), 7.37 (d, 2H), 7.41-7.48 (m, 4H), 7.68 (d, 2H)。
Embodiment 36
5-(4-chloro-phenyl-)-4-cyclopropyl-2-{ [5-(2-ethoxy benzyl)-4 h-1,2,4-triazole-3-base] methyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
50 mg (0.16 mmol) are derived from the compound dissolution of embodiment 21A in 1 ml DMF, add 52 mg (0.24 mmol) 2-(2-ethoxyl phenenyl) ethanamidine-hydrogenchloride, and described mixture is stirred 1 h at 200 DEG C in microwave oven.After cooling, with reactant described in about 1 ml methanol dilution, and by preparation HPLC [method 19] directly separation solution.Obtain 21 mg (28% of theoretical value) title compound.
LC/MS [method 3]: R t=1.14 min; MS [ESIpos]: m/z=451 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.75-0.79 (m, 2H), 0.97-1.02 (m, 2H), 1.44 (t, 3H), 2.97 (m, 1H), 4.09-4.14 (m, 4H), 5.10 (s, 2H), 6.91 (t, 2H), 7.25 (t, 2H), 7.41 (2d, 2H), 7.67 (d, 2H)。
Embodiment 37
5-(4-chloro-phenyl-)-4-cyclopropyl-2-{ [5-(3-luorobenzyl)-4 h-1,2,4-triazole-3-base] methyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 21A by 50 mg (0.16 mmol) obtains 11 mg (16% of theoretical value) title compound.
LC/MS [method 5]: R t=2.16 min; MS [ESIpos]: m/z=425 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.75-0.79 (m, 2H), 0.99-1.05 (m, 2H), 2.98 (m, 1H), 4.10 (s, 2H), 5.15 (s, 2H), 6.93 (m, 1H), 7.00 (d, 1H), 7.07 (d, 1H), 7.23-7.30 (m, 1H), 7.44 (d, 2H), 7.67 (d, 2H)。
Embodiment 38
5-(4-chloro-phenyl-)-4-cyclopropyl-2-{ [5-(2-methoxy-benzyl)-4 h-1,2,4-triazole-3-base] methyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 21A by 50 mg (0.16 mmol) obtains 11 mg (16% of theoretical value) title compound.
LC/MS [method 3]: R t=1.09 min; MS [ESIpos]: m/z=437 (M+H) +.
Embodiment 39
5-(4-chloro-phenyl-)-4-cyclopropyl-2-{ [5-(3-methyl-benzyl)-4 h-1,2,4-triazole-3-base] methyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 21A by 50 mg (0.16 mmol) obtains 11 mg (16% of theoretical value) title compound.
LC/MS [method 3]: R t=1.13 min; MS [ESIpos]: m/z=421 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.73-0.79 (m, 2H), 0.97-1.04 (m, 2H), 2.31 (s, 3H), 2.93-3.01 (m, 1H), 4.07 (s, 2H), 5.13 (s, 2H), 7.04-7.11 (m, 3H), 7.18-7.23 (m, 1H), 7.43 (d, 2H), 7.67 (d, 2H)。
Embodiment 40
2-{ [5-(2-chlorobenzyl)-4 h-1,2,4-triazole-3-base] methyl }-5-(4-chloro-phenyl-)-4-cyclopropyl-2,4-dihydro-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 21A by 50 mg (0.16 mmol) obtains 22 mg (31% of theoretical value) title compound.
LC/MS [method 3]: R t=1.13 min; MS [ESIpos]: m/z=441 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.74-0.79 (m, 2H), 0.99-1.04 (m, 2H), 2.98 (m, 1H), 4.25 (s, 2H), 5.14 (s, 2H), 7.21-7.23 (m, 2H), 7.30-7.32 (m, 1H), 7.38-7.40 (m, 1H), 7.44 (d, 2H), 7.67 (d, 2H)。
Embodiment 41
5-(4-chloro-phenyl-)-4-cyclopropyl-2-{ [5-(2-luorobenzyl)-4 h-1,2,4-triazole-3-base] methyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 21A by 50 mg (0.16 mmol) obtains 11 mg (16% of theoretical value) title compound.
LC/MS [method 5]: R t=2.07 min; MS [ESIpos]: m/z=425 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.74-0.79 (m, 2H), 0.98-1.05 (m, 2H), 2.98 (m, 1H), 4.14 (s, 2H), 5.14 (s, 2H), 7.03-7.12 (m, 2H), 7.21-7.31 (m, 2H), 7.44 (d, 2H), 7.67 (d, 2H)。
Embodiment 42
5-(4-chloro-phenyl-)-2-{ [5-(2,6-dichloro benzyl)-4 h-1,2,4-triazole-3-base] methyl }-4-(4-methoxy-benzyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 17A by 70 mg (0.18 mmol) obtains 36 mg (36% of theoretical value) title compound.
LC/MS [method 3]: R t=1.30 min; MS [ESIpos]: m/z=557 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.78 (s, 3H), 4.47 (s, 2H), 4.86 (s, 2H), 5.22 (s, 2H), 6.82 (d, 2H), 7.06 (d, 2H), 7.18 (t, 1H), 7.33-7.39 (m, 6H)。
Embodiment 43
5-(4-chloro-phenyl-)-2-{ [5-(2,6-dichloro benzyl)-4 h-1,2,4-triazole-3-base] methyl }-4-[(2 r)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 20A by 70 mg (0.18 mmol) obtains 21 mg (21% of theoretical value) title compound.
LC/MS [method 3]: R t=1.23 min; MS [ESIpos]: m/z=548 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.86-3.99 (m, 2H), 4.36-4.45 (m, 2H), 4.56-4.66 (m, 1H), 5.07 (d, 1H), 5.18 (d, 1H), 7.20 (t, 1H), 7.35 (d, 2H), 7.44 (d, 2H), 7.58 (d, 2H)。
Embodiment 44
5-(4-chloro-phenyl-)-4-[(2 r)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 5-[3-(trifluoromethyl) benzyl]-4 h-1,2,4-triazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 20A by 70 mg (0.18 mmol) obtains 21 mg (21% of theoretical value) title compound.
LC/MS [method 5]: R t=2.43 min; MS [ESIpos]: m/z=547 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.86-4.00 (m, 2H), 4.05 (s, 2H), 4.56-4.66 (m, 1H), 5.08 (d, 1H), 5.21 (d, 1H), 7.38-7.47 (m, 4H), 7.50-7.55 (m, 2H), 7.61 (d, 2H)。
Embodiment 45
5-(4-chloro-phenyl-)-4-[(2 r)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-[(5-{2-[3-(trifluoromethyl) phenyl] ethyl }-4 h-1,2,4-triazole-3-base) methyl]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 20A by 70 mg (0.18 mmol) obtains 18 mg (17% of theoretical value) title compound.
LC/MS [method 5]: R t=2.49 min; MS [ESIpos]: m/z=561 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 2.91-2.99 (m, 2H), 3.02-3.10 (m, 2H), 3.87-4.01 (m, 2H), 4.59- 4.69 (m, 1H), 5.09 (d, 1H), 5.25 (d, 1H), 7.32 (d, 1H), 7.38 (m, 1H), 7.41-7.49 (m, 2H), 7.44 (d, 2H), 7.63 (d, 2H)。
Embodiment 46
2-{ [5-(2-chlorobenzyl)-4 h-1,2,4-triazole-3-base] methyl }-5-(4-chloro-phenyl-)-4-[(2 r)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 20A by 70 mg (0.18 mmol) obtains 17 mg (18% of theoretical value) title compound.
LC/MS [method 5]: R t=2.30 min; MS [ESIpos]: m/z=513 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.83-3.97 (m, 2H), 4.04-4.16 (m, 2H), 4.59-4.70 (m, 1H), 5.03 (d, 1H), 5.14 (d, 1H), 7.19-7.25 (m, 3H), 7.36-7.40 (m, 1H), 7.42 (d, 2H), 7.59 (d, 2H)。
Embodiment 47
5-(4-chloro-phenyl-)-2-{ [5-(2-methoxy-benzyl)-4 h-1,2,4-triazole-3-base] methyl }-4-[(2 r)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 20A by 70 mg (0.18 mmol) obtains 16 mg (17% of theoretical value) title compound.
LC/MS [method 5]: R t=2.25 min; MS [ESIpos]: m/z=509 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.86 (s, 3H), 3.83-3.99 (m, 2H), 4.01 (s, 2H), 4.63-4.71 (m, 1H), 5.01 (d, 1H), 5.19 (d, 1H), 6.02 (d, 1H), 6.88-6.95 (m, 2H), 7.13-7.19 (m, 1H), 7.25-7.29 (m, 1H), 7.43 (d, 2H), 7.61 (d, 2H), 11.03-11.15 (br. s, 1H)。
Embodiment 48
5-(4-chloro-phenyl-)-2-{ [5-(2-luorobenzyl)-4 h-1,2,4-triazole-3-base] methyl }-4-[(2 r)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 20A by 100 mg (0.26 mmol) obtains 34 mg (26% of theoretical value) title compound.
LC/MS [method 5]: R t=2.24 min; MS [ESIpos]: m/z=497 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.83-3.98 (m, 2H), 3.97-4.03 (m, 2H), 4.59-4.71 (m, 1H), 5.02 (d, 1H), 5.15 (d, 1H), 6.00 (br. s, 1H), 7.02-7.12 (m, 2H), 7.15-7.21 (m, 1H), 7.22-7.30 (m, 1H), 7.42 (d, 2H), 7.60 (d, 2H), 11.87 (br. s, 1H)。
Embodiment 49
2-{ [5-(2-chlorobenzyl)-4 h-1,2,4-triazole-3-base] methyl }-5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 19A by 138 mg (0.36 mmol) obtains 35 mg (19% of theoretical value) title compound.
LC/MS [method 3]: R t=1.20 min; MS [ESIpos]: m/z=513 and 515 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.89 (dd, 1H), 3.96 (dd, 1H), 4.07-4.18 (m, 2H), 4.58-4.69 (m, 1H), 5.05 + 5.16 (2d, 2H), 5.90 (br. s, 1H), 7.20-7.25 (m, 3H), 7.36-7.41 (m, 1H), 7.43 (d, 2H), 7.57-7.61 (m, 2H), 11.65 (br. s, 1H)。
Embodiment 50
5-(4-chloro-phenyl-)-2-{ [5-(2-luorobenzyl)-4 h-1,2,4-triazole-3-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 19A by 124 mg (0.33 mmol) obtains 37 mg (23% of theoretical value) title compound.
LC/MS [method 3]: R t=1.16 min; MS [ESIpos]: m/z=497 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.89 (dd, 1H), 3.97 (dd, 1H), 3.98-4.08 (m, 2H), 4.61-4.70 (m, 1H), 5.04 + 5.16 (2d, 2H), 5.86 (br. s, 1H), 7.03-7.31 (m, 4H), 7.43 (d, 2H), 7.59 (d, 2H), 11.65 (br. s, 1H)。
Embodiment 51
5-(4-chloro-phenyl-)-2-{ [5-(2,6-dichloro benzyl)-4 h-1,2,4-triazole-3-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 19A by 106 mg (0.28 mmol) obtains 49 mg (32% of theoretical value) title compound.
LC/MS [method 4]: R t=1.08 min; MS [ESIpos]: m/z=547 and 549 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.88 (dd, 1H), 3.96 (dd, 1H), 4.34-4.46 (m, 2H), 4.57-4.67 (m, 1H), 5.03-5.22 (m, 2H), 7.16-7.23 (m, 1H), 7.35 (d, 2H), 7.44 (d, 2H), 7.60 (d, 2H)。
Embodiment 52
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 5-[3-(trifluoromethoxy) benzyl]-4 h-1,2,4-triazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, the compound being derived from embodiment 19A by 120 mg (0.32 mmol) obtains 83 mg (47% of theoretical value) title compound.
LC/MS [method 2]: R t=2.39 min; MS [ESIpos]: m/z=563 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.86-3.96 (m, 2H), 3.95-4.05 (m, 2H), 4.57-4.67 (m, 1H), 5.04-5.24 (m, 2H), 7.09-7.17 (m, 3H), 7.30-7.36 (m, 1H), 7.45 (d, 2H), 7.60 (d, 2H)。
Embodiment 53
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 5-[2-(trifluoromethyl) benzyl]-4 h-1,2,4-triazole-3-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 36 similarly, react the compound that 1190 mg (3.13 mmol) derive from embodiment 19A.In order to carry out aftertreatment, dilute described reaction mixture with 25 ml water, and with each 25 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 932 mg (54% of theoretical value) title compound.
LC/MS [method 4]: R t=1.08 min; MS [ESIpos]: m/z=547 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.83-3.96 (m, 2H), 4.11-4.22 (m, 2H), 4.56-4.68 (m, 1H), 5.00-5.18 (m, 2H), 5.88 (br. s, 1H), 7.25-7.29 (m, 1H), 7.33-7.52 (m, 4H), 7.58 (d, 2H), 7.67 (d, 1H), 11.89 (br. s, 1H)。
Embodiment 54
5-(4-chloro-phenyl-)-2-{ [5-(2-chloro-phenyl-)-4 h-1,2,4-triazole-3-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
1200 mg (3.16 mmol) are derived from the compound dissolution of 19A in 15 ml DMF, add 906 mg (4.74 mmol) 2-spanon-hydrogenchloride, and described mixture is stirred 1 h at 220 DEG C in microwave oven.After cooling, 20 ml 1 N hydrochloric acid are added this reaction mass, and with each 25 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 2:1, then 1:1), be further purified.Obtain 395 mg (80% of theoretical value) title compound, purity is 80%.
LC/MS [method 4]: R t=1.02 min; MS [ESIpos]: m/z=499 and 501 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.85 (dd, 1H), 4.00 (dd, 1H), 4.25-4.37 (m, 1H), 5.00-5.30 (m, 2H), 6.92 (d, 1H), 7.40-7.67 (m, 5H), 7.71-7.81 (m, 3H), 14.27 (br. s, 1H)。
Embodiment 55
(3-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-5-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazol-1-yl) methyl acetate
with
(5-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-3-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazol-1-yl) methyl acetate
( the mixture of positional isomers)
350 mg (0.57 mmol) are derived from the compound dissolution of embodiment 30 in 9 ml DMF, and add 27 mg (0.68 mmol) sodium hydride (60%, in paraffin).By described mixture at stirring at room temperature 10 min.Then add 68 mg (0.63 mmol) methyl chloroacetate, stir 30 min at 40 DEG C.In order to carry out aftertreatment, 10 ml water are added in this mixture, and with each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product; Here can not separation point position isomer.Obtain the mixture of the title compound of 310 mg (88% of theoretical value) position isomerism, it can be used as such mixture to react further (see embodiment 58 and 59).
LC/MS [method 5]: R t=2.52 min; MS [ESIpos]: m/z=619 (M+H) +and R t=2.60 min; MS [ESIpos]: m/z=619 (M+H) +.
Embodiment 56 and embodiment 57
[5-(2-chloro-phenyl-)-3-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-1 h-1,2,4-triazol-1-yl] methyl acetate ( positional isomers 1)
with
[3-(2-chloro-phenyl-)-5-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydro-1H-1,2,4-triazol-1-yl } methyl)-1 h-1,2,4-triazol-1-yl] methyl acetate ( positional isomers 2)
395 mg (0.79 mmol) are derived from the compound dissolution of embodiment 54 in 10 ml DMF, and add 38 mg (0.95 mmol) sodium hydride (60%, in paraffin).By described mixture at stirring at room temperature 10 min.Then add 94 mg (0.87 mmol) methyl chloroacetate, and described mixture is stirred 30 min at 40 DEG C.After being cooled to room temperature, without any further aftertreatment, by chromatography [method 19], the complete separation point position of reaction mixture described in direct purification isomer.Obtain 71 mg (16% of theoretical value) positional isomers 1 (embodiment 56) and 210 mg (46% of theoretical value) positional isomers 2 (embodiment 57).
embodiment 56:
LC/MS [method 4]: R t=1.09 min; MS [ESIpos]: m/z=571 and 573 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.69 (s, 3H), 3.94 (dd, 1H), 4.05 (dd, 1H), 4.55-4.64 (m, 1H), 4.80 (s, 2H), 5.14-5.33 (m, 2H), 5.36 (d, 1H), 7.34-7.40 (m, 1H), 7.42-7.52 (m, 5H), 7.54-7.60 (m, 2H)。
embodiment 57:
LC/MS [method 4]: R t=1.15 min; MS [ESIpos]: m/z=571 and 573 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.74 (s, 3H), 3.92 (dd, 1H), 3.99 (dd, 1H), 4.55-4.65 (m, 1H), 4.89 (d, 1H), 5.16-5.39 (m, 4H), 7.28-7.34 (m, 2H), 7.42-7.50 (m, 3H), 7.59-7.64 (m, 2H), 7.85-7.91 (m, 1H)。
Embodiment 58 and embodiment 59
(3-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-5-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazol-1-yl) acetic acid ( positional isomers 1)
with
(5-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-3-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazol-1-yl) acetic acid ( positional isomers 2)
The compound (mixture as positional isomers) 310 mg (0.50 mmol) being derived from embodiment 55 is dissolved in 5 ml methyl alcohol, and adds 0.85 ml (0.85 mmol) 1 N lithium hydroxide aqueous solution.By described mixture at stirring at room temperature 45 min.Then under reduced pressure remove the solvent in described mixture, be dissolved in 10 ml water, and neutralize with 0.85 ml (0.85 mmol) 1 N hydrochloric acid.With mixture described in each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 16] purification of crude product separation positional isomers.Obtain 81 mg (27% of theoretical value) positional isomers 1 (embodiment 58) and 83 mg (27% of theoretical value) positional isomers 2 (embodiment 59).
embodiment 58:
LC/MS [method 2]: R t=2.27 min; MS [ESIpos]: m/z=605 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.81 (dd, 1H), 3.97 (dd, 1H), 4.26 (s, 3H), 4.86-4.97 (m, 2H), 5.06 (s, 2H), 6.89 (d, 1H), 7.32 (d, 1H), 7.45-7.52 (m, 1H), 7.56-7.65 (m, 3H), 7.69-7.76 (m, 3H), 13.35 (br. s, 1H)。
embodiment 59:
LC/MS [method 2]: R t=2.37 min; MS [ESIpos]: m/z=605 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.79 (dd, 1H), 3.93 (dd, 1H), 4.12 (s, 2H), 4.24-4.30 (m, 1H), 5.07-5.22 (m, 4H), 6.89 (d, 1H), 7.40-7.48 (m, 2H), 7.55-7.66 (m, 3H), 7.67-7.75 (m, 3H), 13.26 (br. s, 1H)。
Embodiment 60
[5-(2-chloro-phenyl-)-3-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-1 h-1,2,4-triazol-1-yl] acetic acid
65 mg (0.11 mmol) are derived from the compound dissolution of embodiment 56 in 5 ml methyl alcohol, and add 0.26 ml (0.26 mmol) 1 N lithium hydroxide aqueous solution.By described mixture at stirring at room temperature 30 min.Then under reduced pressure remove the solvent in described mixture, be dissolved in 10 ml water, and neutralize with 0.85 ml (0.85 mmol) 1 N hydrochloric acid.With mixture described in each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.Obtain 57 mg (76% of theoretical value) title compound, purity is 84%.
LC/MS [method 4]: R t=0.95 min; MS [ESIpos]: m/z=557 and 559 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.85 (dd, 1H), 3.96-4.03 (m, 1H), 4.24-4.36 (m, 1H), 4.86 (s, 2H), 5.03-5.14 (m, 2H), 6.90 (d, 1H), 7.47-7.52 (m, 2H), 7.55-7.68 (m, 4H), 7.76 (d, 2H), 13.30 (br. s, 1H)。
Embodiment 61
[3-(2-chloro-phenyl-)-5-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-1 h-1,2,4-triazol-1-yl] acetic acid
With the preparation of the compound in embodiment 60 similarly, react the compound that 205 mg (0.36 mmol) derive from embodiment 57.Obtain 198 mg (94% of theoretical value) title compound, purity is 93%.
LC/MS [method 2]: R t=2.20 min; MS [ESIpos]: m/z=557 and 559 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.81 (dd, 1H), 3.96 (dd, 1H), 4.24-4.38 (m, 1H), 5.20-5.37 (m, 4H), 6.90 (br. s, 1H), 7.42-7.47 (m, 2H), 7.55-7.58 (m, 1H), 7.62 (d, 2H), 7.74 (d, 2H), 7.82-7.87 (m, 1H), 13.38 (br. s, 1H)。
Embodiment 62
2-(3-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-5-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazol-1-yl) ethanamide ( racemoid)
The compound that 85 mg (0.14 mmol) derive from embodiment 58 is put into 2.5 ml DMF in advance, and adds 23 mg (0.17 mmol) HOBt and 35 mg (0.18 mmol) EDC.After stirring at room temperature 20 min, add 0.3 ml (5.65 mmol) ammonia solution (in water 32%), and by described reaction mass at stirring at room temperature 16 h.Then remove the excess of ammonia in described reaction solution in a vacuum, add about 3 ml water, and with mixture described in each 5 ml extraction into ethyl acetate 3 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 58 mg (69% of theoretical value) target compound.
LC/MS [method 5]: R t=2.22 min; MS [ESIpos]: m/z=604 (M+H) +.
By the preparation HPLC [method 17] gone up mutually in chirality, the racemoid (58 mg) deriving from embodiment 62 is separated into enantiomer.Obtain the 27 mg first enantiomer 1 (embodiment 63) of wash-out and the enantiomer 2 (embodiment 64) of the more late wash-out of 29 mg:
Embodiment 63
2-(3-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-5-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazol-1-yl) ethanamide ( enantiomer 1)
The enantiomer of first wash-out in the racemoid of embodiment 62 is separated.
Chirality HPLC [method 18]: R t=6.57 min.
1H-NMR (400 MHz, DMSO-d 6): δ= 3.81 (dd, 1H), 3.97 (dd, 1H), 4.22-4.33 (m, 3H), 4.83 (s, 2H), 4.85-4.95 (m, 2H), 6.89 (d, 1H), 7.31-7.38 (m, 2H), 7.45-7.50 (m, 1H), 7.55-7.64 (m, 3H), 7.65-7.76 (m, 4H)。
Embodiment 64
2-(3-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-5-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazol-1-yl) ethanamide ( enantiomer 2)
The enantiomer of last wash-out in the racemoid of embodiment 62 is separated.
Chirality HPLC [method 18]: R t=7.70 min.
1H-NMR (400 MHz, DMSO-d 6): δ= 3.81 (dd, 1H), 3.97 (dd, 1H), 4.22-4.33 (m, 3H), 4.83 (s, 2H), 4.85-4.95 (m, 2H), 6.89 (d, 1H), 7.31-7.38 (m, 2H), 7.45-7.50 (m, 1H), 7.55-7.64 (m, 3H), 7.65-7.76 (m, 4H)。
Embodiment 65
2-(5-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-3-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazol-1-yl) ethanamide ( racemoid)
The compound that 95 mg (0.16 mmol) derive from embodiment 59 is put into 2.5 ml DMF in advance, and adds 25 mg (0.19 mmol) HOBt and 39 mg (0.20 mmol) EDC.After stirring at room temperature 20 min, add 0.3 ml (5.65 mmol) ammonia solution (in water 32%), and by described reaction mass at stirring at room temperature 16 h.Then remove the excess of ammonia in described reaction solution in a vacuum, add about 3 ml water, and with mixture described in each 5 ml extraction into ethyl acetate 3 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 58 mg (61% of theoretical value) target compound.
LC/MS [method 5]: R t=2.32 min; MS [ESIpos]: m/z=604 (M+H) +.
By the preparation HPLC [method 12] gone up mutually in chirality, the racemoid (58 mg) deriving from embodiment 65 is separated into enantiomer.Obtain the 28 mg first enantiomer 1 (embodiment 66) of wash-out and the enantiomer 2 (embodiment 67) of the more late wash-out of 28 mg:
Embodiment 66
2-(5-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-3-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazol-1-yl) ethanamide ( enantiomer 1)
The enantiomer of first wash-out in the racemoid of embodiment 65 is separated.
Chirality HPLC [method 13]: R t=4.78 min.
1H-NMR (400 MHz, DMSO-d 6): δ= 3.79 (dd, 1H), 3.94 (dd, 1H), 4.10 (s, 2H), 4.24-4.35 (m, 1H), 4.93 (s, 2H), 5.09-5.19 (m, 2H), 6.87 (d, 1H), 7.34 (s, 1H), 7.40-7.48 (m, 2H), 7.55-7.75 (m, 7H)。
Embodiment 67
2-(5-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-3-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazol-1-yl) ethanamide ( enantiomer 2)
The enantiomer of last wash-out in the racemoid of embodiment 65 is separated.
Chirality HPLC [method 13]: R t=6.35 min.
1H-NMR (400 MHz, DMSO-d 6): δ= 3.79 (dd, 1H), 3.94 (dd, 1H), 4.10 (s, 2H), 4.24-4.35 (m, 1H), 4.93 (s, 2H), 5.09-5.19 (m, 2H), 6.87 (d, 1H), 7.34 (s, 1H), 7.40-7.48 (m, 2H), 7.55-7.75 (m, 7H)。
Embodiment 68
2-[5-(2-chloro-phenyl-)-3-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-1 h-1,2,4-triazol-1-yl] ethanamide
The compound that 54 mg (0.10 mmol) derive from embodiment 60 is put into 4 ml DMF in advance, and adds 19 mg (0.13 mmol) HOBt and 24 mg (0.03 mmol) EDC.After stirring at room temperature 10 min, add 0.1 ml (1.93 mmol) ammonia solution (in water 32%), and by described mixture at stirring at room temperature 16 h.Then remove the excess of ammonia in described reaction solution in a vacuum, add about 3 ml water, and with mixture described in each 5 ml extraction into ethyl acetate 3 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 27 mg (46% of theoretical value) target compound.
LC/MS [method 3]: R t=1.08 min; MS [ESIpos]: m/z=556 and 558 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.85 (dd, 1H), 4.00 (dd, 1H), 4.25-4.37 (m, 1H), 4.64 (s, 2H), 5.07 (s, 2H), 6.91 (d, 1H), 7.24 (br. s, 1H), 7.46-7.67 (m, 7H), 7.76 (d, 2H)。
Embodiment 69
2-[3-(2-chloro-phenyl-)-5-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-1 h-1,2,4-triazol-1-yl] ethanamide
With the preparation of the compound in embodiment 68 similarly, react the compound that 100 mg (0.18 mmol) derive from embodiment 61.Obtain 67 mg (67% of theoretical value) title compound.
LC/MS [method 3]: R t=1.14 min; MS [ESIpos]: m/z=556 and 558 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.81 (dd, 1H), 3.96 (dd, 1H), 4.28-4.34 (m, 1H), 5.04-5.14 (m, 2H), 5.22-5.32 (m, 2H), 6.86 (d, 1H), 7.39-7.46 (m, 2H), 7.52-7.57 (m, 1H), 7.62 (d, 2H), 7.72-7.78 (m, 3H), 7.83-7.88 (m, 1H), 7.95 (s, 1H)。
Embodiment 70
5-(4-chloro-phenyl-)-2-{ [5-(2-chloro-phenyl-)-4 h-1,2,4-triazole-3-base] methyl }-4-(3,3,3-trifluoro propyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 54 similarly, react the compound that 50 mg (0.14 mmol) derive from embodiment 23A.Obtain 8 mg (11% of theoretical value) title compound.
LC/MS [method 4]: R t=1.06 min; MS [ESIpos]: m/z=483 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 2.59-2.69 (m, 2H), 4.00 (t, 2H), 5.13 (s, 2H), 7.42-7.51 (m, 2H), 7.56-7.71 (m, 5H), 7.75-7.81 (m, 1H), 14.25 (br. s, 1H)。
Embodiment 71
5-(4-chloro-phenyl-)-2-{ [5-(2,6-dichloro benzyl)-4 h-1,2,4-triazole-3-base] methyl }-4-(3,3,3-trifluoro propyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 54 similarly, react the compound that 50 mg (0.14 mmol) derive from embodiment 23A.Obtain 18 mg (25% of theoretical value) title compound.
LC/MS [method 4]: R t=1.10 min; MS [ESIpos]: m/z=531 and 533 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 2.55-2.69 (m, 2H), 3.97 (t, 2H), 4.23-4.34 (m, 2H), 4.95 (s, 2H), 7.31-7.37 (m, 1H), 7.48 (d, 2H), 7.60-7.68 (m, 4H), 13.70 (br. s, 1H)。
Embodiment 72
2-{ [5-(2-chlorobenzyl)-4 h-1,2,4-triazole-3-base] methyl }-5-(4-chloro-phenyl-)-4-(3,3,3-trifluoro propyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 54 similarly, react the compound that 48 mg (0.13 mmol) derive from embodiment 23A.Obtain 22 mg (33% of theoretical value) title compound.
LC/MS [method 4]: R t=1.07 min; MS [ESIpos]: m/z=497 and 499 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 2.56-2.69 (m, 2H), 3.98 (t, 2H), 4.12 (s, 2H), 4.97 (s, 2H), 7.25-7.34 (m, 3H), 7.40-7.46 (m, 1H), 7.59-7.68 (m, 5H)。
Embodiment 73
5-(4-chloro-phenyl-)-2-{ [5-(2-chloro-phenyl-)-2-thienyl] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound and 134 mg (0.41 mmol) cesium carbonate that 85 mg (0.28 mmol) are derived from embodiment 5A are suspended in 5 ml acetonitriles, and add the compound that 113 mg (0.28 mmol) derive from embodiment 56A.Described mixture is stirred 20 h under reflux.In order to carry out aftertreatment, described mixture being cooled to room temperature, removing acetonitrile in a vacuum, and 10 ml water are added in resistates.With mixture described in each 10 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 4 mg (3% of theoretical value) target compound.
LC/MS [method 4]: R t=1.32 min; MS [ESIpos]: m/z=514 and 516 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 4.00 (dd, 1H), 4.22-4.35 (m, 1H), 5.16-5.26 (m, 2H), 6.91 (br. s, 1H), 7.16 (d, 1H), 7.32 (d, 1H), 7.34-7.44 (m, 2H), 7.53-7.65 (m, 4H), 7.76 (d, 2H)。
Embodiment 74
5-(4-chloro-phenyl-)-2-{ [5-(2,3-dichlorophenyl)-2-thienyl] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound and 142 mg (0.44 mmol) cesium carbonate that 67 mg (0.22 mmol) are derived from embodiment 5A are suspended in 4 ml acetonitriles, and add the compound that 70 mg (0.28 mmol) derive from embodiment 57A.Described mixture is stirred 2 h under reflux.In order to carry out aftertreatment, described mixture being cooled to room temperature, removing acetonitrile in a vacuum, and 10 ml water are added in resistates.With mixture described in each 10 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 29 mg (24% of theoretical value) target compound.
LC/MS [method 4]: R t=1.37 min; MS [ESIpos]: m/z=548 and 550 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.99 (dd, 1H), 4.24-4.34 (m, 1H), 5.18-5.27 (m, 2H), 6.90 (d, 1H), 7.17 (d, 1H), 7.33 (d, 1H), 7.42 (t, 1H), 7.57 (dd, 1H), 7.61-7.67 (m, 3H), 7.74-7.79 (m, 2H)。
Embodiment 75
5-(4-chloro-phenyl-)-2-{ [5-(2,3-difluorophenyl)-2-thienyl] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
Under an argon, the compound and 45 mg (0.29 mmol) 2, the 3-difluorophenyl boronic acid that 84 mg (0.19 mmol) are derived from embodiment 30A are dissolved in 2 ml toluene.Then add 9 mg (0.01 mmol) three (dibenzalacetone) two palladium, 8 mg (0.02 mmol) 2-dicyclohexyl phosphino--2'-( n,N-dimethylamino) biphenyl and 81 mg (0.38 mmol) potassiumphosphate, and under argon by described mixture at 110 DEG C of heating 14 h.In order to carry out aftertreatment, diluting described mixture at room temperature 10 ml ethyl acetate and 10 ml water, isolating organic phase, and also use each 10 ml extraction into ethyl acetate aqueous phase 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 25 mg (24% of theoretical value) target compound.
LC/MS [method 2]: R t=2.72 min; MS [ESIpos]: m/z=516 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.78-4.07 (m, 2H), 4.23-4.39 (m, 1H), 5.10-5.26 (m, 2H), 6.86-6.95 (m, 1H), 6.99-7.05 (m, 1H), 7.17-7.59 (m, 4H), 7.60-7.66 (m, 1H), 7.73-7.80 (m, 2H), 7.83-7.90 (m, 1H)。
Embodiment 76
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 2-[2-(trifluoromethyl) phenyl]-1,3-thiazoles-5-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
Under an argon, the compound and 40 mg (0.21 mmol) 2-(trifluoromethyl) phenyl-boron dihydroxide that 62 mg (0.14 mmol) are derived from embodiment 31A are dissolved in 2 ml toluene.Then add 6.5 mg (0.007 mmol) three (dibenzalacetone) two palladium, 5.6 mg (0.014 mmol) 2-dicyclohexyl phosphino--2'-( n,N-dimethylamino) biphenyl and 60 mg (0.28 mmol) potassiumphosphate, and described mixture is heated to 110 DEG C under argon and continues 48 h.In order to carry out aftertreatment, diluting described mixture at room temperature 10 ml ethyl acetate and 10 ml water, isolating organic phase, and also use each 10 ml extraction into ethyl acetate aqueous phase 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 10 mg (13% of theoretical value) target compound.
LC/MS [method 2]: R t=2.54 min; MS [ESIpos]: m/z=549 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 4.00 (dd, 1H), 4.22-4.34 (m, 1H), 5.29-5.38 (m, 2H), 6.90 (d, 1H), 7.61-7.67 (m, 2H), 7.71-7.83 (m, 5H), 7.93 (d, 1H), 7.96 (s, 1H)。
Embodiment 77
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 5-[2-(trifluoromethyl) phenyl]-1,3-thiazoles-2-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
40 mg (0.13 mmol) are derived from the compound dissolution of embodiment 5A in 7 ml acetonitriles, and add the compound that 66 mg (0.20 mmol) cesium carbonate and 42 mg (0.13 mmol) derive from embodiment 89A.Described mixture is stirred 1 h at 80 DEG C.In order to carry out aftertreatment, described mixture being cooled to room temperature, with 5 ml methanol dilution, and filtering.Concentrated filtrate in a vacuum, then by chromatography [method 19] purification of crude product.Obtain 47 mg (66% of theoretical value) target compound.
LC/MS [method 3]: R t=2.48 min; MS [ESIpos]: m/z=549 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.86 (dd, 1H), 4.02 (dd, 1H), 4.24-4.34 (m, 1H), 5.35-5.45 (m, 2H), 6.92 (s, 1H), 7.58-7.66 (m, 3H), 7.66-7.80 (m, 5H), 7.90 (d, 1H)。
Embodiment 78
5-(4-chloro-phenyl-)-2-{ [5-(2-chloro-phenyl-)-1,3-thiazoles-2-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 77 similarly, 70 mg (0.23 mmol) are derived from, and compound that the compound of embodiment 5A and 66 mg (0.23 mmol) derive from embodiment 88A reacts.Obtain 65 mg (55% of theoretical value) title compound.
LC/MS [method 4]: R t=1.23 min; MS [ESIpos]: m/z=515 and 517 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.86 (dd, 1H), 4.02 (dd, 1H), 4.24-4.35 (m, 1H), 5.39 (s, 2H), 6.92 (br. s, 1H), 7.44 (dd, 2H), 7.58-7.72 (m, 4H), 7.78 (d, 2H), 8.06 (s, 1H)。
Embodiment 79
2-{ [5-(the chloro-2-fluorophenyl of 3-)-1,3-thiazoles-2-base] methyl }-5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 77 similarly, 70 mg (0.23 mmol) are derived from, and compound that the compound of embodiment 5A and 70 mg (0.23 mmol) derive from embodiment 90A reacts.Obtain 90 mg (72% of theoretical value) title compound.
LC/MS [method 3]: R t=1.44 min; MS [ESIpos]: m/z=533 and 535 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.86 (dd, 1H), 4.02 (dd, 1H), 4.25-4.35 (m, 1H), 5.37-5.43 (m, 2H), 6.92 (s, 1H), 7.30-7.36 (m, 1H), 7.60-7.67 (m, 3H), 7.75-7.82 (m, 3H), 8.27 (s, 1H)。
Embodiment 80
5-(4-chloro-phenyl-)-2-({ 5-[the fluoro-3-of 2-(trifluoromethyl) phenyl]-1,3-thiazoles-2-base } methyl)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 77 similarly, 55 mg (0.18 mmol) are derived from, and compound that the compound of embodiment 5A and 61 mg (0.18 mmol) derive from embodiment 91A reacts.Obtain 55 mg (52% of theoretical value) title compound.
LC/MS [method 4]: R t=1.26 min; MS [ESIpos]: m/z=567 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.86 (dd, 1H), 4.02 (dd, 1H), 4.25-4.35 (m, 1H), 5.41 (s, 2H), 6.92 (s, 1H), 7.52 (t, 1H), 7.64 (d, 2H), 7.75-7.84 (m, 3H), 8.17 (t, 1H), 8.33 (s, 1H)。
Embodiment 81
5-(4-chloro-phenyl-)-2-{ [5-(2-chloro-phenyl-)-4-(trifluoromethyl)-1,3-thiazoles-2-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 77 similarly, 40 mg (0.13 mmol) are derived from, and compound that the compound of embodiment 5A and 46 mg (0.13 mmol) derive from embodiment 92A reacts.Obtain 58 mg (76% of theoretical value) title compound.
LC/MS [method 4]: R t=1.32 min; MS [ESIpos]: m/z=583 and 585 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.86 (dd, 1H), 4.02 (dd, 1H), 4.24-4.34 (m, 1H), 5.44-5.49 (m, 2H), 6.90 (br. s, 1H), 7.44-7.50 (m, 1H), 7.53-7.60 (m, 2H), 7.61-7.68 (m, 3H), 7.75-7.80 (m, 2H)。
Embodiment 82
5-(4-chloro-phenyl-)-2-{ [2-(2-chloro-phenyl-)-1,3-oxazole-5-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 77 similarly, 113 mg (0.37 mmol) are derived from, and compound that the compound of embodiment 5A and 100 mg (0.37 mmol) derive from embodiment 54A reacts.Obtain 23 mg (12% of theoretical value) title compound.
LC/MS [method 6]: R t=2.44 min; MS [ESIpos]: m/z=499 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.82 (dd, 1H), 3.98 (dd, 1H), 4.25-4.33 (m, 1H), 5.15-5.25 (m, 2H), 6.88 (d, 1H), 7.41 (s, 1H), 7.48-7.57 (m, 2H), 7.60-7.66 (m, 3H), 7.72-7.76 (m, 2H), 7.92 (dd, 1H)。
Embodiment 83
5-(4-chloro-phenyl-)-2-{ [2-(2,3-dichlorophenyl)-1,3-oxazole-5-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 77 similarly, 49 mg (0.16 mmol) derive from the compound that the compound of embodiment 5A and 49 mg (0.16 mmol) derive from embodiment 55A and react.Obtain 35 mg (40% of theoretical value) title compound.
LC/MS [method 4]: R t=1.23 min; MS [ESIpos]: m/z=533 and 535 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.82 (dd, 1H), 3.98 (dd, 1H), 4.22-4.34 (m, 1H), 5.17-5.26 (m, 2H), 6.89 (s, 1H), 7.45 (s, 1H), 7.53 (t, 1H), 7.61-7.65 (m, 2H), 7.72-7.76 (m, 2H), 7.84 (dd, 1H), 7.88 (dd, 1H)。
Embodiment 84
5-(4-chloro-phenyl-)-4-cyclopropyl-2-({ 5-[3-(trifluoromethyl) benzyl]-1,3-thiazoles-2-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound and 47 mg (0.12 mmol) 4-p-methoxy-phenyl phosphonodithioic acid acid anhydride (Lawesson reagent) that 52 mg (0.11 mmol) are derived from embodiment 27A are dissolved in 1 ml THF, and described mixture is stirred 16 h at 70 DEG C.After being cooled to room temperature, between 10 ml t-butyl methyl ether and 10 ml water, distribute described mixture.Isolate organic phase, with water and the saturated nacl aqueous solution washing of each 10 ml, through dried over sodium sulfate, filter, and concentrate in a vacuum.By preparation HPLC [method 19] Purification.Obtaining 50 mg (97% of theoretical value) title compound, is colorless solid.
MS [ESIpos]: m/z = 491 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.71-0.81 (m, 2H), 0.97-1.06 (m, 2H), 2.94-3.03 (m, 1H), 4.18 (s, 2H), 5.25 (s, 2H), 7.35-7.55 (m, 6H), 7.69 (d, 2H)。
Embodiment 85
5-(4-chloro-phenyl-)-4-cyclopropyl-2-({ 5-[3-(trifluoromethyl) benzyl]-1 h-imidazoles-2-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
50 mg (0.10 mmol) are derived from the compound dissolution of embodiment 27A in 1 ml DMF, and mix with 23 mg (0.30 mmol) ammonium acetate, and described mixture is stirred 15 min at 200 DEG C in microwave oven.After cooling, add other 30 mg (0.39 mmol) ammonium acetate, and described mixture is stirred other 30 min at 200 DEG C in microwave oven.After being cooled to room temperature, between 10 ml ethyl acetate and 10 ml water, distribute described mixture.Isolate organic phase, with water and the saturated nacl aqueous solution washing of each 10 ml, through dried over sodium sulfate, filter, and concentrate in a vacuum.By preparation HPLC [method 19] Purification.Obtaining 17 mg (35% of theoretical value) target compound, is micro-yellow coloured resin.
MS [ESIpos]: m/z = 474 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.65-0.82 (br. m, 2H), 0.97-1.09 (m, 2H), 2.92-3.03 (m, 1H), 3.98 (s, 2H), 5.10 (s, 2H), 7.33-7.58 (m, 6H), 7.68 (d, 2H), 10.19 (s, 1H)。
Embodiment 86
5-(4-chloro-phenyl-)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2-({ 5-[2-(trifluoromethyl) phenyl] pyridin-3-yl } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound and 43 mg (0.23 mmol) 2-(trifluoromethyl) phenyl-boron dihydroxide that 72 mg (0.15 mmol) are derived from embodiment 28A are dissolved in 2 ml dioxs.Make argon conductance cross this solution 10 min, under argon, then add 8.7 mg (0.008 mmol) tetrakis triphenylphosphine palladium (0).Described mixture is heated to boiling, and under argon, adds 0.15 ml (0.30 mmol) 2 N aqueous sodium carbonate.Described mixture is stirred 20 h under reflux.After being cooled to room temperature, dilute described mixture with 10 ml water, and with each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 36 mg (44% of theoretical value) target compound.
LC/MS [method 4]: R t=1.18 min; MS [ESIpos]: m/z=543 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.99 (dd, 1H), 4.23-4.35 (m, 1H), 5.09-5.20 (m, 2H), 6.90 (d, 1H), 7.47 (d, 1H), 7.59-7.65 (m, 2H), 7.65-7.81 (m, 5H), 7.89 (d, 1H), 8.49 (d, 1H), 8.62 (d, 1H)。
Embodiment 87
5-(4-chloro-phenyl-)-2-{ [5-(2-chloro-phenyl-) pyridin-3-yl] methyl }-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 86 similarly, make 72 mg (0.15 mmol) derive from the compound of embodiment 28 A and 59 mg (0.23 mmol) 2-chlorophenylboronic acid reacts each other.Obtain 49 mg (64% of theoretical value) target compound.
LC/MS [method 4]: R t=1.16 min; MS [ESIpos]: m/z=509 and 511 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.99 (dd, 1H), 4.24-4.36 (m, 1H), 5.10-5.20 (m, 2H), 6.90 (d, 1H), 7.44-7.50 (m, 3H), 7.58-7.65 (m, 3H), 7.75 (d, 2H), 7.86 (t, 1H), 8.57-8.62 (m, 2H)。
Embodiment 88
5-(4-chloro-phenyl-)-2-{ [5-(2,3-dichlorophenyl) pyridin-3-yl] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 86 similarly, make 34 mg (0.07 mmol) derive from the compound of embodiment 29A and 20 mg (0.10 mmol) 2,3-dichlorophenyl boric acid reacts each other.Obtain 26 mg (69% of theoretical value) target compound.
LC/MS [method 4]: R t=1.21 min; MS [ESIpos]: m/z=543 and 545 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.99 (dd, 1H), 4.26-4.34 (m, 1H), 5.10-5.20 (m, 2H), 6.90 (d, 1H), 7.42-7.53 (m, 2H), 7.60-7.65 (m, 2H), 7.71-7.78 (m, 3H), 7.86 (t, 1H), 8.61 (dd, 2H)。
Embodiment 89
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 2-[2-(trifluoromethyl) phenyl] pyridin-4-yl } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
145 mg (0.46 mmol) are derived from the compound dissolution of embodiment 64A in 3 ml acetonitriles, and add compound and 224 mg (0.69 mmol) cesium carbonate that 141 mg (0.46 mmol) derive from embodiment 5A.Described mixture is stirred 16 h at 60 DEG C.After being cooled to room temperature, filter out solid, and rinse with a small amount of acetonitrile.In a vacuum, filtrate is reduced to the volume of about 2 ml, adds 0.1 ml 1 N hydrochloric acid, and by chromatography [method 19] directly purified product.Obtain 49 mg (20% of theoretical value) target compound.
LC/MS [method 4]: R t=1.15 min; MS [ESIpos]: m/z=543 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.85 (dd, 1H), 4.01 (dd, 2H), 4.28-4.35 (m, 1H), 5.09-5.20 (m, 2H), 6.90 (d, 1H), 7.32 (dd, 1H), 7.41 (s, 1H), 7.52 (d, 1H), 7.61-7.66 (m, 2H), 7.68 (d, 1H), 7.73-7.79 (m, 3H), 7.85 (d, 1H), 8.63 (d, 1H)。
Embodiment 90
5-(4-chloro-phenyl-)-2-{ [2-(2-chloro-phenyl-) pyridin-4-yl] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 89 similarly, 261 mg (0.85 mmol) are derived from, and compound that the compound of embodiment 5A and 240 mg (0.85 mmol) derive from embodiment 65A reacts each other.Obtain 249 mg (54% of theoretical value) target compound.
LC/MS [method 3]: R t=1.28 min; MS [ESIpos]: m/z=509 and 511 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.87 (dd, 1H), 4.01 (dd, 1H), 4.26-4.39 (m, 1H), 5.10-5.20 (m, 2H), 6.90 (d, 1H), 7.30 (d, 1H), 7.41-7.50 (m, 2H), 7.55-7.60 (m, 3H), 7.64 (d, 2H), 7.77 (d, 2H), 8.68 (d, 1H)。
Embodiment 91
5-(4-chloro-phenyl-)-2-{ [2-(2,3-dichlorophenyl) pyridin-4-yl] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
81 mg (0.26 mmol) are derived from the compound dissolution of embodiment 66A in 3 ml acetonitriles, and add compound and 125 mg (0.38 mmol) cesium carbonate that 79 mg (0.26 mmol) derive from embodiment 5A.Described mixture is stirred 2 h at 65 DEG C, and at other 16 h of stirring at room temperature.Then filter out solid, and rinse with a small amount of acetonitrile.Concentrated filtrate in a vacuum, and by chromatography [method 19] direct purification.Obtain 79 mg (56% of theoretical value) target compound.
LC/MS [method 4]: R t=1.21 min; MS [ESIpos]: m/z=543 and 545 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.85 (dd, 1H), 4.01 (dd, 1H), 4.28-4.35 (m, 1H), 5.10-5.21 (m, 2H), 6.91 (d, 1H), 7.34 (dd, 1H), 7.45-7.52 (m, 2H), 7.57 (s, 1H), 7.61-7.66 (m, 2H), 7.71-7.79 (m, 3H), 8.67 (d, 1H)。
Embodiment 92
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 2-[2-(trifluoromethyl) phenyl] pyrimidine-4-yl } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound (purity about 20%) 303 mg (0.19 mmol) being derived from embodiment 80A is dissolved in 2 ml acetonitriles, and adds compound and 93 mg (0.29 mmol) cesium carbonate that 65 mg (0.21 mmol) derive from embodiment 5A.Described mixture is stirred 2.5 h at 60 DEG C, and at other 96 h of stirring at room temperature.Then filter out solid, and rinse with a small amount of acetonitrile.Concentrated filtrate in a vacuum, and by chromatography [method 19] direct purification.Obtain 19 mg target compounds, to the further chromatogram purification (elutriant: cyclohexane/ethyl acetate 7:3, then 1:1) that it carries out on silica gel.Obtain 8 mg (7% of theoretical value) target compound.
LC/MS [method 3]: R t=1.32 min; MS [ESIpos]: m/z=544 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.86 (dd, 1H), 4.01 (dd, 1H), 4.31-4.35 (m, 1H), 5.13-5.26 (m, 2H), 6.93 (d, 1H), 7.39 (d, 1H), 7.61-7.67 (m, 2H), 7.69-7.83 (m, 5H), 7.88 (d, 1H), 8.93 (d, 1H)。
Embodiment 93
5-(4-chloro-phenyl-)-2-{ [2-(2-chloro-phenyl-) pyrimidine-4-yl] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound (purity about 20%) 259 mg (0.18 mmol) being derived from embodiment 81A is dissolved in 2 ml acetonitriles, and adds compound and 89 mg (0.27 mmol) cesium carbonate that 62 mg (0.21 mmol) derive from embodiment 5A.Described mixture is stirred 2.5 h at 60 DEG C, and at other 96 h of stirring at room temperature.Then filter out solid, and rinse with a small amount of acetonitrile.Concentrated filtrate in a vacuum, and by chromatography [method 19] direct purification.Obtain 31 mg target compounds, to the further chromatogram purification (elutriant: cyclohexane/ethyl acetate 7:3, then 1:1) that it carries out on silica gel.Obtain 23 mg (22% of theoretical value) target compound.
LC/MS [method 4]: R t=1.13 min; MS [ESIpos]: m/z=510 and 512 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.87 (dd, 1H), 4.02 (dd, 1H), 4.28-4.38 (m, 1H), 5.16-5.26 (m, 2H), 6.93 (d, 1H), 7.36 (d, 1H), 7.44-7.54 (m, 2H), 7.56-7.60 (m, 1H), 7.61-7.66 (m, 2H), 7.71-7.79 (m, 3H), 8.94 (d, 1H)。
Embodiment 94
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 6-[2-(trifluoromethyl) phenyl] pyrimidine-4-yl } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
37 mg (0.12 mmol) are derived from the compound dissolution of embodiment 82A in 2 ml acetonitriles, and add compound and 57 mg (0.18 mmol) cesium carbonate that 39 mg (0.13 mmol) derive from embodiment 5A.Described mixture is stirred 2.5 h at 60 DEG C.After being cooled to room temperature, filter out solid, and rinse with a small amount of acetonitrile.Concentrated filtrate in a vacuum, and by chromatography [method 19] direct purification.To the further chromatogram purification (elutriant: cyclohexane/ethyl acetate 4:1, then 3:2) that the product obtained carries out on silica gel.Obtain 28 mg (41% of theoretical value) target compound.
LC/MS [method 6]: R t=2.34 min; MS [ESIpos]: m/z=544 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.86 (dd, 1H), 4.01 (dd, 1H), 4.27-4.34 (m, 1H), 5.17-5.29 (m, 2H), 6.91 (d, 1H), 7.55 (s, 1H), 7.59 (d, 1H), 7.63 (d, 2H), 7.72-7.78 (m, 3H), 7.80-7.85 (m, 1H), 7.91 (d, 1H), 9.24 (d, 1H)。
Embodiment 95
5-(4-chloro-phenyl-)-2-{ [6-(2-chloro-phenyl-) pyrimidine-4-yl] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 94 similarly, 27 mg (0.10 mmol) are derived from, and compound that the compound of embodiment 83A and 32 mg (0.11 mmol) derive from embodiment 5A reacts each other.Obtain 29 mg (54% of theoretical value) target compound.
LC/MS [method 4]: R t=1.15 min; MS [ESIpos]: m/z=510 and 512 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.86 (dd, 1H), 4.02 (dd, 1H), 4.27-4.35 (m, 1H), 5.19-5.29 (m, 2H), 6.91 (d, 1H), 7.48-7.59 (m, 2H), 7.60-7.69 (m, 4H), 7.72 (d, 1H), 7.74-7.80 (m, 2H), 9.27 (d, 1H)。
Embodiment 96
5-(4-chloro-phenyl-)-2-{ [6-(2,3-dichlorophenyl) pyrimidine-4-yl] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 94 similarly, 23 mg (0.07 mmol) are derived from, and compound that the compound of embodiment 84A and 24 mg (0.08 mmol) derive from embodiment 5A reacts each other.Obtain 29 mg (66% of theoretical value) target compound.
LC/MS [method 6]: R t=2.54 min; MS [ESIpos]: m/z=544 and 546 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.86 (dd, 1H), 4.02 (dd, 1H), 4.26-4.38 (m, 1H), 5.18-5.30 (m, 2H), 6.92 (s, 1H), 7.51-7.56 (m, 1H), 7.57-7.60 (m, 1H), 7.61-7.65 (m, 2H), 7.71 (d, 1H), 7.74-7.79 (m, 2H), 7.81 (dd, 1H), 9.29 (d, 1H)。
Embodiment 97
5-(4-chloro-phenyl-)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2-({ 1-[3-(trifluoromethyl) benzyl]-1 h-1,2,3-triazoles-4-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
29 mg (0.12 mmol) 3-(trifluoromethyl) bromotoluene is put into 1 ml acetonitrile in advance, and adds 8 mg (0.12 mmol) sodiumazide.By described mixture at stirring at room temperature 1 h.Then the compound that 0.24 mg (0.012 mmol) copper acetate dihydrate (II) and 50 mg (0.14 mmol) derive from embodiment 13A is added.By the mixture that obtains stirring at room temperature 11 days.Then by reaction mixture described in a small amount of filtered through silica gel, with about 10 ml eluent ethyl acetate products, and concentrated filtrate in a vacuum.By chromatography [method 19] purification of crude product.Obtain 52 mg (65% of theoretical value) target compound.
LC/MS [method 4]: R t=1.13 min; MS [ESIpos]: m/z=547 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.91-3.99 (m, 1H), 3.98-4.05 (m, 1H), 4.46-4.56 (m, 1H), 5.15 (q, 2H), 5.34 (d, 1H), 5.51-5.61 (m, 2H), 7.41-7.59 (m, 8H), 7.63 (d, 1H)。
Embodiment 98
5-(4-chloro-phenyl-)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2-({ 1-[2-(trifluoromethyl) benzyl]-1 h-1,2,3-triazoles-4-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 97 similarly, the compound that 50 mg (0.14 mmol) derive from embodiment 13A produces 54 mg (68% of theoretical value) title compound.
LC/MS [method 4]: R t=1.13 min; MS [ESIpos]: m/z=547 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.91-3.99 (m, 1H), 3.99-4.06 (m, 1H), 4.46-4.57 (m, 1H), 5.16 (q, 2H), 5.31 (d, 1H), 5.72 (s, 2H), 7.20 (d, 1H), 7.42-7.58 (m, 7H), 7.72 (d, 1H)。
Embodiment 99
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 1-[2-(trifluoromethyl) phenyl]-1 h-1,2,3-triazoles-4-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
20 mg (0.31 mmol) sodiumazide is put into 1 ml methyl alcohol in advance, and adds 58 mg (0.31 mmol) 2-(trifluoromethyl) phenyl-boron dihydroxide and 6 mg (0.03 mmol) copper acetate dihydrate (II).By described mixture at stirring at room temperature 18 h.Then the compound 0.9 ml water, 30 mg (0.15 mmol) L-AA sodium salt and 117 mg (0.34 mmol) being derived from embodiment 14A adds in described mixture.By described mixture at other 18 h of stirring at room temperature.In order to carry out aftertreatment, with mixture described in 10 ml water and 10 ml diluted ethyl acetate, and under agitation add 5 ml 0.1 N aqueous sodium hydroxide solutions.After being separated, with other 3 times of each 10 ml extraction into ethyl acetate aqueous phase.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 5:1, then 1:2) purification of crude product.Obtain 117 mg (71% of theoretical value) target compound.
LC/MS [method 3]: R t=1.26 min; MS [ESIpos]: m/z=533 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.99 (dd, 1H), 4.28-4.34 (m, 1H), 5.12-5.23 (m, 2H), 6.91 (d, 1H), 7.63 (d, 2H), 7.68-7.79 (m, 3H), 7.81-7.96 (m, 2H), 8.03 (d, 1H), 8.51 (s, 1H)。
Embodiment 100
5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2-({ 1-[3-(trifluoromethyl) phenyl]-1 h-1,2,3-triazoles-4-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 99 similarly, the compound that 117 mg (0.34 mmol) derive from embodiment 14A produces 138 mg (84% of theoretical value) title compound.
LC/MS [method 3]: R t=1.33 min; MS [ESIpos]: m/z=533 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.99 (dd, 1H), 4.27-4.38 (m, 1H), 5.13-5.22 (m, 2H), 6.91 (d, 1H), 7.59-7.65 (m, 2H), 7.73-7.79 (m, 2H), 7.81-7.90 (m, 2H), 8.24-8.32 (m, 2H), 9.02 (s, 1H)。
Embodiment 101
5-(4-chloro-phenyl-)-2-{ [1-(2-chloro-phenyl-)-1 h-1,2,3-triazoles-4-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 99 similarly, the compound that 75 mg (0.22 mmol) derive from embodiment 14A produces 56 mg (55% of theoretical value) title compound.
LC/MS [method 4]: R t=1.09 min; MS [ESIpos]: m/z=499 and 501 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.99 (dd, 1H), 4.28-4.35 (m, 1H), 5.13-5.22 (m, 2H), 6.91 (d, 1H), 7.55-7.70 (m, 5H), 7.74-7.80 (m, 3H), 8.54 (s, 1H)。
Embodiment 102
5-(4-chloro-phenyl-)-2-{ [1-(2,3-dichlorophenyl)-1 h-1,2,3-triazoles-4-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
124 mg (0.36 mmol) are derived from the compound dissolution of embodiment 14A in 2 ml acetonitriles, and add 0.6 mg (0.003 mmol) copper acetate dihydrate (II) and 56 mg (0.30 mmol) 1-azido--2,3-dichlorobenzene.Described mixture is stirred 2 h at 50 DEG C.In order to carry out aftertreatment, crude mixture is cooled to room temperature, and by a small amount of filtered through silica gel.With eluent ethyl acetate, and concentrate the solution obtained in a vacuum.Then by chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 1:1), purification of crude product.Obtain 61 mg (31% of theoretical value) target compound.
LC/MS [method 4]: R t=1.13 min; MS [ESIpos]: m/z=533 and 535 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.99 (dd, 1H), 4.29-4.34 (m, 1H), 5.13-5.23 (m, 2H), 6.91 (d, 1H), 7.58-7.66 (m, 3H), 7.69 (dd, 1H), 7.77 (d, 2H), 7.92 (dd, 1H), 8.59 (s, 1H)。
Embodiment 103
(2-chloro-phenyl-) [4-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-1 h-1,2,3-triazoles-1-base] methyl acetate
361 mg (1.37 mmol) bromo (2-chloro-phenyl-) methyl acetate is put into 10 ml acetonitriles in advance, and adds 89 mg (1.37 mmol) sodiumazide.By described mixture at stirring at room temperature 1 h.Then the compound that 2.7 mg (0.14 mmol) copper acetate dihydrate (II) and 569 mg (1.64 mmol) derive from embodiment 14A is added.The mixture obtained is stirred 48 h at 50 DEG C.Then by reaction mixture described in a small amount of filtered through silica gel, with about 10 ml eluent ethyl acetate products, and concentrated filtrate in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 8:1 → 6:1 → 4:1 → 2:1 → 1:1) purification of crude product.Obtain 496 mg (53% of theoretical value) target compound.
LC/MS [method 4]: R t=1.13 min; MS [ESIpos]: m/z=571 and 573 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.76 (s, 3H), 3.81 (dd, 1H), 3.96 (dd, 1H), 4.25-4.32 (m, 1H), 5.02-5.12 (m, 2H), 6.88 (dd, 1H), 7.12 (s, 1H), 7.39-7.51 (m, 3H), 7.57 (d, 1H), 7.62 (d, 2H), 7.72 (d, 2H), 8.25 (d, 1H)。
Embodiment 104
(2-chloro-phenyl-) [4-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-1 h-1,2,3-triazoles-1-base] acetic acid
49 mg (0.09 mmol) are derived from the compound dissolution of embodiment 103 in 2 ml methyl alcohol, and add 193 μ l (0.19 mmol) 1 N lithium hydroxide aqueous solution.By described mixture at stirring at room temperature 30 min.Then in a vacuum except desolventizing, resistates is dissolved in 5 ml water, and with this solution of 5 ml extraction into ethyl acetate 1 time.Abandon organic phase.With 0.2 ml 1 N hcl acidifying aqueous phase, and with each 5 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.Obtain 40 mg (83% of theoretical value) target compound.
LC/MS [method 4]: R t=0.95 min; MS [ESIpos]: m/z=557 and 559 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.80 (dd, 1H), 3.96 (dd, 1H), 4.26-4.31 (m, 1H), 5.03-5.10 (m, 2H), 6.90 (dd, 1H), 6.94 (s, 1H), 7.42-7.51 (m, 3H), 7.54-7.58 (m, 1H), 7.59-7.65 (m, 2H), 7.73 (d, 2H), 8.22 (d, 1H)。
Embodiment 105
2-(2-chloro-phenyl-)-2-[4-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-1 h-1,2,3-triazoles-1-base] ethanamide
The compound that 25 mg (0.045 mmol) derive from embodiment 104 is put into 1 ml DMF in advance, and adds 9 mg (0.058 mmol) HOBt and 11 mg (0.058 mmol) EDC.After stirring at room temperature 10 min, add 0.5 ml (0.90 mmol) ammonia solution (35% in water), and by described reaction mass at stirring at room temperature 16 h.Then without any further aftertreatment, by chromatography [method 19] directly reaction mixture described in purifying.Obtain 10 mg (40% of theoretical value) target compound.
LC/MS [method 4]: R t=0.99 min; MS [ESIpos]: m/z=556 and 558 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.75-3.85 (m, 1H), 3.91-4.00 (m, 1H), 4.23-4.31 (m, 1H), 5.03 (s, 2H), 6.76 (s, 1H), 6.90 (d, 1H), 7.47 (br. s, 3H), 7.55 (m, 1H), 7.59-7.65 (m, 2H), 7.71 (d, 3H), 7.85 (m, 1H), 8.08 (br. s, 1H)。
Embodiment 106
5-(4-chloro-phenyl-)-2-({ 1-[1-(2-chloro-phenyl-)-2-hydroxyethyl]-1 h-1,2,3-triazoles-4-base } methyl)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
48 mg (0.084 mmol) are derived from the compound dissolution of embodiment 103 in 2 ml THF, and add the 1 M solution of 88 μ l (0.088 mmol) lithium aluminum hydride in THF at-10 DEG C.After adding completely, by described mixture at stirring at room temperature 1 h.In order to carry out aftertreatment, add the saturated aqueous sodium potassium tartrate of 2 ml in room temperature, and with mixture described in 5 ml extraction into ethyl acetate.Wash organic phase 1 time with 5 ml saturated nacl aqueous solutions, through dried over mgso, filter, and concentrate in a vacuum.By chromatography [method 19] purification of crude product.Obtain 8 mg (18% of theoretical value) target compound.
LC/MS [method 2]: R t=2.20 min; MS [ESIpos]: m/z=543 and 545 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.81 (dd, 1H), 3.93-4.04 (m, 2H), 4.21-4.32 (m, 1H), 5.02-5.12 (m, 2H), 5.45 (dd, 1H), 6.14 (dd, 1H), 6.90 (d, 1H), 7.32-7.41 (m, 3H), 7.50-7.54 (m, 1H), 7.60-7.65 (m, 2H), 7.71-7.76 (m, 2H), 8.34 (s, 1H)。
Embodiment 107
[4-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-1 h-1,2,3-triazoles-1-base] [2-(trifluoromethyl) phenyl] ethyl acetate
The compound (purity about 30%) 158 mg (0.15 mmol) being derived from embodiment 98A puts into 2 ml acetonitriles in advance, and adds 9.9 mg (0.15 mmol) sodiumazide.By described mixture at stirring at room temperature 1 h.Then the compound that 0.3 mg (0.002 mmol) copper acetate dihydrate (II) and 63 mg (0.18 mmol) derive from embodiment 14A is added.The mixture obtained is stirred 20 h at 50 DEG C.Then by reaction mixture described in a small amount of filtered through silica gel, with about 10 ml eluent ethyl acetates, and concentrated filtrate in a vacuum.By chromatography [method 19] purification of crude product.Obtain 9 mg (8% of theoretical value) target compound.
LC/MS [method 3]: R t=1.36 min; MS [ESIpos]: m/z=619 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 1.13 (t, 3H), 3.81 (dd, 1H), 3.96 (dd, 1H), 4.17-4.31 (m, 3H), 5.01-5.11 (m, 2H), 6.89 (dd, 1H), 6.93 (d, 1H), 7.59-7.75 (m, 6H), 7.77-7.88 (m, 2H), 8.29 (d, 1H)。
Embodiment 108
5-(4-chloro-phenyl-)-4-cyclopropyl-2-({ 4-[2-(trifluoromethyl) phenyl]-1 h-1,2,3-triazoles-1-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
60 mg (0.21 mmol) are derived from the compound dissolution of embodiment 122A in 2 ml acetonitriles, add 14 mg (0.21 mmol) sodiumazide, and by described mixture at stirring at room temperature 1 h.Then 0.4 mg (0.002 mmol) copper acetate dihydrate (II) and 43 mg (0.25 mmol) 1-ethynyl-2-(trifluoromethyl) benzene is added.By the mixture that obtains at stirring at room temperature 20 h.In order to carry out aftertreatment, add 10 ml ethyl acetate, and with each 5 ml water, described mixture is washed 2 times.Organic phase, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 48 mg (45% of theoretical value) target compound.
LC/MS [method 4]: R t=1.15 min; MS [ESIpos]: m/z=461 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 0.57-0.63 (m, 2H), 0.85-0.92 (m, 2H), 3.19 (m, 1H), 6.44 (s, 2H), 7.58-7.68 (m, 3H), 7.74-7.84 (m, 4H), 7.87 (d, 1H), 8.42 (s, 1H)。
Embodiment 109
5-(4-chloro-phenyl-)-4-cyclopropyl-2-({ 4-[3-(trifluoromethyl) phenyl]-1 h-1,2,3-triazoles-1-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of the compound in embodiment 108 similarly, the compound that 60 mg (0.21 mmol) derive from embodiment 122A produces 21 mg (21% of theoretical value) title compound.
LC/MS [method 4]: R t=1.19 min; MS [ESIpos]: m/z=461 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 0.59-0.64 (m, 2H), 0.85-0.92 (m, 2H), 3.18 (m, 1H), 6.39 (s, 2H), 7.57-7.62 (m, 2H), 7.66-7.73 (m, 2H), 7.78-7.83 (m, 2H), 8.19-8.26 (m, 2H), 8.91 (s, 1H)。
Embodiment 110
5-(4-chloro-phenyl-)-2-{ [1-(2-chloro-phenyl-)-1 h-imidazol-4 yl] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
19 mg (0.06 mmol) are derived from the compound dissolution of embodiment 5A in 5 ml acetonitriles, and add the compound that 17 mg (0.13 mmol) salt of wormwood and 17 mg (0.06 mmol) derive from embodiment 42A.Described mixture is stirred 2 h, then at stirring at room temperature 20 h at 65 DEG C.In order to carry out aftertreatment, add 5 ml water, and with mixture described in each 10 ml extraction into ethyl acetate 2 times.Wash organic phase 1 time with 5 ml saturated nacl aqueous solutions, through dried over sodium sulfate, filter, and concentrate in a vacuum.By chromatography [method 19] purification of crude product.Obtain 4 mg (12% of theoretical value) target compound.
LC/MS [method 4]: R t=1.04 min; MS [ESIpos]: m/z=498 and 500 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.99 (dd, 1H), 4.27-4.37 (m, 1H), 4.89-4.96 (m, 2H), 6.92 (br. s, 1H), 7.37 (s, 1H), 7.47-7.57 (m, 3H), 7.62 (d, 2H), 7.67-7.72 (m, 1H), 7.76 (d, 2H), 7.87 (s, 1H)。
Embodiment 111
5-(4-chloro-phenyl-)-2-{ [1-(2-chloro-phenyl-)-1 h-pyrazoles-4-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
27 mg (0.09 mmol) are derived from the compound dissolution of embodiment 5A in 2 ml acetonitriles, and add the compound that 58 mg (0.18 mmol) cesium carbonate and 24 mg (0.09 mmol) derive from embodiment 43A.Described mixture is stirred 2 h, then at stirring at room temperature 20 h at 65 DEG C.In order to carry out aftertreatment, add 5 ml water, and with mixture described in each 10 ml extraction into ethyl acetate 2 times.Wash organic phase 1 time with 5 ml saturated nacl aqueous solutions, through dried over sodium sulfate, filter, and concentrate in a vacuum.By chromatography [method 19] purification of crude product.Obtain 25 mg (56% of theoretical value) target compound.
LC/MS [method 4]: R t=1.11 min; MS [ESIpos]: m/z=498 and 500 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.82 (dd, 1H), 3.98 (dd, 1H), 4.31 (d, 1H), 4.92-5.01 (m, 2H), 6.90 (d, 1H), 7.45-7.52 (m, 2H), 7.55-7.70 (m, 4H), 7.73-7.79 (m, 3H), 8.16 (s, 1H)。
Embodiment 112
4-allyl group-5-(4-chloro-phenyl-)-2-{ [1-(2,6-dichloro benzyl)-1 h-imidazoles-5-base] methyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
41 mg (0.17 mmol) are derived from the compound dissolution of embodiment 12A in 2 ml DMF, and add compound and 85 mg (0.26 mmol) cesium carbonate that 48 mg (0.17 mmol) derive from embodiment 40A.Described mixture is stirred 16 h at 80 DEG C.After being cooled to room temperature, with reaction mixture described in 1 ml methanol dilution, and by chromatography [method 19] direct purification.Obtain 4 mg (5% of theoretical value) target compound.
LC/MS [method 5]: R t=2.01 min; MS [ESIpos]: m/z=474 and 476 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 4.35 (d, 2H), 4.98 (s, 2H), 5.09 (d, 1H), 5.23 (d, 1H), 5.29-5.42 (m, 2H), 5.83-5.96 (m, 1H), 7.07 (s, 1H), 7.22-7.29 (m, 1H), 7.34-7.43 (m, 4H), 7.50-7.61 (m, 3H)。
Embodiment 113
4-allyl group-5-(4-chloro-phenyl-)-2-{ [1-(2,6-dichloro benzyl)-4-nitro-1 h-imidazoles-2-base] methyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
110 mg (0.47 mmol) are derived from the compound dissolution of embodiment 12A in 10 ml DMF, and add compound and 229 mg (0.70 mmol) cesium carbonate that 150 mg (0.47 mmol) derive from embodiment 41A.Described mixture is stirred 16 h at 80 DEG C.After being cooled to room temperature, described reaction mixture being added frozen water to about 25 ml, and stir 10 min.This causes sedimentary formation, and suction filtration goes out described throw out, and washes with water.Dry described solid under a high vacuum.Obtain 120 mg (44% of theoretical value) target compound, purity is 90%.
LC/MS [method 3]: R t=1.35 min; MS [ESIpos]: m/z=519 and 521 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 4.31-4.45 (m, 2H), 5.03 (d, 1H), 5.16 (d, 1H), 5.32 (s, 2H), 5.63 (s, 2H), 5.80-5.92 (m, 1H), 7.50-7.56 (m, 1H), 7.57-7.67 (m, 6H), 7.77 (s, 1H)。
Embodiment 114
5-(4-chloro-phenyl-)-4-cyclopropyl-2-({ 1-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazole-5-base } alkylsulfonyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
37 mg (0.10 mmol) are derived from the compound dissolution of embodiment 93A in 3 ml methylene dichloride, and add 21 μ l (0.13 mmol) n,N-diisopropylethylamine.Then 30 mg (0.13 mmol) 2-(trifluoromethyl) bromotoluene be dissolved in 1 ml methylene dichloride is added, and by described mixture at stirring at room temperature 48 h.In order to carry out aftertreatment, concentrated described mixture in a vacuum, and by chromatography [method 19] purification of crude product.Obtain 33 mg (63% of theoretical value) target compound.
LC/MS [method 5]: R t=2.57 min; MS [ESIpos]: m/z=525 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.72-0.78 (m, 2H), 0.97-1.04 (m, 2H), 2.94 (tt, 1H), 5.60 (s, 2H), 7.40 (d, 1H), 7.46 (d, 2H), 7.48-7.60 (m, 2H), 7.69-7.75 (m, 3H), 8.11 (s, 1H)。
Embodiment 115
5-(4-chloro-phenyl-)-4-cyclopropyl-2-{ [1-(2,6-dichloro benzyl)-1 h-1,2,4-triazole-5-base] alkylsulfonyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
37 mg (0.10 mmol) are derived from the compound dissolution of embodiment 93A in 3 ml methylene dichloride, and add 21 μ l (0.13 mmol) n,N-diisopropylethylamine.Then 30 mg (0.13 mmol) 2, the 6-dichloro benzyl bromine be dissolved in 1 ml methylene dichloride is added, and by described mixture at stirring at room temperature 20 h.In order to carry out aftertreatment, concentrated described mixture in a vacuum, and by chromatography [method 19] purification of crude product.Obtain 39 mg (74% of theoretical value) target compound.
LC/MS [method 2]: R t=2.41 min; MS [ESIpos]: m/z=525 and 527 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 0.73-0.79 (m, 2H), 0.98-1.05 (m, 2H), 2.95 (tt, 1H), 5.72 (s, 2H), 7.30-7.36 (m, 1H), 7.37-7.43 (m, 2H), 7.46 (d, 2H), 7.72 (d, 2H), 8.10 (s, 1H)。
Embodiment 116
5-(4-chloro-phenyl-)-4-(4-methoxy-benzyl)-2-({ 1-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazole-5-base } alkylsulfonyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
334 mg (0.75 mmol) are derived from the compound dissolution of embodiment 94A in 5 ml methylene dichloride, and add 154 μ l (0.93 mmol) n,N-diisopropylethylamine.Then 223 mg (0.93 mmol) 2-(trifluoromethyl) bromotoluene be dissolved in 0.5 ml methylene dichloride is added, and by described mixture at stirring at room temperature 20 h.In order to carry out aftertreatment, concentrated described mixture in a vacuum, and by chromatography [method 19] purification of crude product.Obtain 245 mg (54% of theoretical value) target compound.
LC/MS [method 3]: R t=1.44 min; MS [ESIpos]: m/z=605 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.77 (s, 3H), 4.81 (s, 2H), 5.61 (s, 2H), 6.78 (d, 2H), 7.03 (d, 2H), 7.35-7.43 (m, 5H), 7.48-7.58 (m, 2H), 7.74 (d, 1H), 8.12 (s, 1H)。
Embodiment 117
5-(4-chloro-phenyl-)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2-({ 1-[2-(trifluoromethyl) benzyl]-1 h-1,2,4-triazole-5-base } alkylsulfonyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound 50 mg (0.10 mmol) being derived from embodiment 95A is dissolved in 0.5 ml DMF together with 50 mg (0.16 mmol) cesium carbonate, and add 30 mg (0.16 mmol) 3-bromo-1,1,1-trifluoro propane-2-alcohol.Then described mixture is stirred 8 h at 75 DEG C.In order to carry out aftertreatment, with reaction mixture described in 0.5 ml dilution in acetonitrile, and by chromatography [method 19] direct purification.Obtain 15 mg (22% of theoretical value) target compound.
LC/MS [method 5]: R t=2.61 min; MS [ESIpos]: m/z=597 (M+H) +
1H-NMR (400 MHz, CDCl 3): δ= 3.86 (dd, 1H), 3.95 (dd, 1H), 4.28-4.34 (m, 1H), 4.68-4.76 (m, 1H), 5.62 (s, 2H), 7.42 (d, 1H), 7.47 (d, 2H), 7.50-7.61 (m, 2H), 7.68 (d, 2H), 7.74 (d, 1H), 8.15 (s, 1H)。
Embodiment 118
4-allyl group-5-(4-chloro-phenyl-)-2-{ [1-(2,6-dichloro benzyl)-4-methyl isophthalic acid h-imidazoles-5-base] methyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
with
4-allyl group-5-(4-chloro-phenyl-)-2-{ [1-(2,6-dichloro benzyl)-5-methyl isophthalic acid h-imidazol-4 yl] methyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone (position different structure mixture)
The compound and 88 mg (0.37 mmol) 2, the 6-dichloro benzyl bromine that 110 mg (0.33 mmol) are derived from embodiment 96A are dissolved in 5 ml DMF together, and add 130 mg (0.40 mmol) cesium carbonate.Described mixture is stirred 6 h at 60 DEG C.After being cooled to room temperature, with reaction mixture described in 1 ml methanol dilution, and by chromatography [method 19] direct purification.Obtain the mixture of the title compound of the position isomerism of 9 mg (6% of theoretical value) about 1:1 ratio.
LC/MS [method 3]: R t=1.08 min; MS [ESIpos]: m/z=488/490 (M+H) +and R t=1.10 min; MS [ESIpos]: m/z=488/490 (M+H) +
1h-NMR (400 MHz, CDCl 3): δ=2.38 and 2.42 (2s, 3H), 4.30-4.41 (m, 2H), 4.97 and 5.49 (2s, 2H), 5.05-5.32 (m, 4H), 5.84-5.95 (m, 1H), 6.97 and 7.13 (2s, 1H), 7.24-7.47 (m, 5H), 7.49-7.58 (m, 2H).
Embodiment 119
5-(4-chloro-phenyl-)-4-cyclopropyl-2-({ 4-methyl isophthalic acid-[3-(trifluoromethyl) benzyl]-1 h-imidazoles-5-base } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
with
5-(4-chloro-phenyl-)-4-cyclopropyl-2-({ 5-methyl isophthalic acid-[3-(trifluoromethyl) benzyl]-1 h-imidazol-4 yl } methyl)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone (position different structure mixture)
The compound 40 mg (0.12 mmol) being derived from embodiment 97A is dissolved in 3 ml DMF together with 88 mg (0.37 mmol) 3-(trifluoromethyl) bromotoluene, and adds 47 mg (0.15 mmol) cesium carbonate.Described mixture is stirred 3 h at 60 DEG C.In order to carry out aftertreatment, after being cooled to room temperature, dilute described mixture with 5 ml water, and with mixture described in each 10 ml extraction into ethyl acetate 3 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.Resistates is dissolved in 4 ml methyl alcohol, and carries out purifying by chromatography [method 19].Obtain the mixture of the title compound of the position isomerism of 20 mg (32% of theoretical value) about 1:1.8 ratio.
LC/MS [method 5]: R t=1.75 min; MS [ESIpos]: m/z=488 (M+H) +and R t=1.89 min; MS [ESIpos]: m/z=488 (M+H) +
1h-NMR (400 MHz, CDCl 3): δ=0.53-0.59 and 0.70-0.76 (2m, 2H), 0.91-1.03 (m, 2H), 2.21 and 2.40 (2s, 3H), 2.80 and 2.94 (2tt, 1H), 4.82 and 4.93 (2s, 2H), 5.30 and 5.43 (2s, 2H), 7.11 and 7.19 (2d, 1H), 7.31-7.52 (m, 6H), 7.54-7.59 and 7.66-7.70 (2m, 2H).
Embodiment 120
5-(4-chloro-phenyl-)-4-cyclopropyl-2-[2-(2-methylphenoxy) benzyl]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
100 mg (0.25 mmol) are derived from the compound of embodiment 99A, 53 mg (0.49 mmol) ortho-cresol and 91 mg (0.74 mmol) 4- n,N-Dimethylamino pyridine is dissolved in 5 ml acetonitriles, and adds 39 mg (0.62 mmol) copper powder and 49 mg (0.62 mmol) cupric oxide (II).Described mixture is stirred 16 h at 85 DEG C.In order to carry out aftertreatment, described mixture is cooled to room temperature, and by filtered through silica gel, with a small amount of ethyl acetate rinse resistates.Concentrated filtrate in a vacuum, then by chromatography [method 19] purification of crude product.Obtain 25 mg (23% of theoretical value) target compound.
LC/MS [method 4]: R t=1.33 min; MS [ESIpos]: m/z=432 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 0.34-0.44 (m, 2H), 0.76-0.85 (m, 2H), 2.18 (s, 3H), 3.05 (tt, 1H), 5.00 (s, 2H), 6.59-6.71 (m, 2H), 7.01 (t, 1H), 7.05-7.15 (m, 2H), 7.24-7.32 (m, 2H), 7.35 (d, 1H), 7.56 (d, 2H), 7.71 (d, 2H)。
Embodiment 121
2-[(2'-chloro-4-fluorine biphenyl-3-base) methyl]-5-(4-chloro-phenyl-)-4-cyclopropyl-2,4-dihydro-3 h-1,2,4-triazole-3-ketone
With the preparation of embodiment 122 similarly, make 89 mg (0.15 mmol) derive from the compound of embodiment 100A and 59 mg (0.23 mmol) 2-chlorophenylboronic acid reacts.Obtain 51 mg (73% of theoretical value) target compound.
LC/MS [method 4]: R t=1.35 min; MS [ESIpos]: m/z=454 and 456 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 0.54-0.61 (m, 2H), 0.84-0.91 (m, 2H), 3.14-3.20 (m, 1H), 5.04 (s, 2H), 7.28-7.36 (m, 1H), 7.37-7.47 (m, 5H), 7.53-7.59 (m, 3H), 7.77 (d, 2H)。
Embodiment 122
2-[(2'-chlordiphenyl-3-base) methyl]-5-(4-chloro-phenyl-)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
The compound and 59 mg (0.23 mmol) the 2-chlorophenylboronic acid that 72 mg (0.15 mmol) are derived from embodiment 101A are dissolved in 2 ml dioxs.Make argon conductance cross this solution 10 min, and under argon, add 8.7 mg (0.008 mmol) tetrakis triphenylphosphine palladium (0).Described mixture is heated to boiling, and under argon, adds 0.15 ml (0.30 mmol) 2 N aqueous sodium carbonate.Then described mixture is stirred 20 h under reflux.After being cooled to room temperature, dilute described mixture with 10 ml water, and with each 15 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 51 mg (61% of theoretical value) target compound.
LC/MS [method 4]: R t=1.30 min; MS [ESIpos]: m/z=508 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 4.00 (dd, 1H), 4.26-4.34 (m, 1H), 5.01-5.13 (m, 2H), 6.88 (d, 1H), 7.32-7.50 (m, 7H), 7.54-7.59 (m, 1H), 7.62 (d, 2H), 7.74 (d, 2H)。
Embodiment 123
5-(4-chloro-phenyl-)-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-2-{ [2'-(trifluoromethyl) biphenyl-3-base] methyl }-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of embodiment 122 similarly, make 72 mg (0.15 mmol) derive from the compound of embodiment 101A and 43 mg (0.23 mmol) 2-(trifluoromethyl) phenyl-boron dihydroxide reacts.Obtain 49 mg (58% of theoretical value) target compound.
LC/MS [method 4]: R t=1.31 min; MS [ESIpos]: m/z=542 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.84 (dd, 1H), 3.99 (dd, 1H), 4.26-4.32 (m, 1H), 4.99-5.12 (m, 2H), 6.88 (d, 1H), 7.22-7.29 (m, 2H), 7.34-7.47 (m, 3H), 7.57-7.64 (m, 3H), 7.67-7.76 (m, 3H), 7.83 (d, 1H)。
Embodiment 124
5-(4-chloro-phenyl-)-2-[(2', 3'-DCBP-3-base) methyl]-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of embodiment 122 similarly, make 94 mg (0.20 mmol) derive from compound and 56 mg (0.23 mmol) 2, the 3-dichlorophenyl acid reaction of embodiment 102A.Obtain 48 mg (45% of theoretical value) target compound.
LC/MS [method 3]: R t=1.54 min; MS [ESIpos]: m/z=542 and 544 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.84 (dd, 1H), 4.00 (dd, 1H), 4.27-4.35 (m, 1H), 5.02-5.12 (m, 2H), 6.89 (d, 1H), 7.34-7.42 (m, 4H), 7.42-7.51 (m, 2H), 7.60-7.64 (m, 2H), 7.68 (dd, 1H), 7.72-7.77 (m, 2H)。
Embodiment 125
5-(4-chloro-phenyl-)-2-{ [the fluoro-2'-of 5-(trifluoromethyl) biphenyl-3-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of embodiment 122 similarly, make 59 mg (0.12 mmol) derive from the compound of embodiment 103A and 36 mg (0.18 mmol) 2-(trifluoromethyl) phenyl-boron dihydroxide reacts.Obtain 43 mg (64% of theoretical value) target compound.
LC/MS [method 4]: R t=1.34 min; MS [ESIpos]: m/z=560 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.84 (dd, 1H), 3.99 (dd, 1H), 4.26-4.33 (m, 1H), 5.03-5.14 (m, 2H), 6.89 (d, 1H), 7.10-7.23 (m, 3H), 7.43 (d, 1H), 7.59-7.68 (m, 3H), 7.70-7.77 (m, 3H), 7.85 (d, 1H)。
Embodiment 126
2-[(2'-chloro-5-fluorine biphenyl-3-base) methyl]-5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of embodiment 122 similarly, make 59 mg (0.12 mmol) derive from the compound of embodiment 103A and 28 mg (0.18 mmol) 2-chlorophenylboronic acid reacts.Obtain 34 mg (54% of theoretical value) target compound.
LC/MS [method 4]: R t=1.34 min; MS [ESIpos]: m/z=526 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.84 (dd, 1H), 4.00 (dd, 1H), 4.26-4.34 (m, 1H), 5.04-5.15 (m, 2H), 6.90 (d, 1H), 7.16-7.21 (m, 1H), 7.22-7.28 (m, 2H), 7.40-7.47 (m, 3H), 7.55-7.65 (m, 3H), 7.75 (d, 2H)。
Embodiment 127
2-[(the bromo-2'-chlordiphenyl of 5--3-base) methyl]-5-(4-chloro-phenyl-)-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of embodiment 91 similarly, 109 mg (0.36 mmol) are derived from, and compound that the compound of embodiment 5A and 128 mg (0.36 mmol) derive from embodiment 117A reacts.Obtain 148 mg (68% of theoretical value) target compound.
LC/MS [method 4]: R t=1.40 min; MS [ESIpos]: m/z=586,588 and 590 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.97-4.03 (m, 1H), 4.26-4.34 (m, 1H), 5.03-5.13 (m, 2H), 6.88 (d, 1H), 7.40-7.47 (m, 4H), 7.55-7.60 (m, 3H), 7.61-7.65 (m, 2H), 7.71-7.77 (m, 2H)。
Embodiment 128
5-(4-chloro-phenyl-)-2-[(chloro-1,1':3', the 1''-terphenyl-5'-base of 2,2''-bis-) methyl]-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
With the preparation of embodiment 91 similarly, 105 mg (0.34 mmol) are derived from, and compound that the compound of embodiment 5A and 135 mg (0.35 mmol) derive from embodiment 118A reacts.Obtain 115 mg (53% of theoretical value) target compound.
LC/MS [method 4]: R t=1.47 min; MS [ESIpos]: m/z=618 and 620 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 4.00 (dd, 1H), 4.26-4.32 (m, 1H), 5.08-5.20 (m, 2H), 6.86 (d, 1H), 7.39-7.52 (m, 9H), 7.55-7.65 (m, 4H), 7.74 (d, 2H)。
Embodiment 129
The chloro-3-{ of 2'-[3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl } biphenyl-4-methyl-formiate
With the preparation of embodiment 122 similarly, make 265 mg (0.50 mmol) derive from the compound of embodiment 104A and 194 mg (0.74 mmol) 2-chlorophenylboronic acid reacts.Obtain 54 mg (19% of theoretical value) purity be 98% target compound and 167 mg (49% of theoretical value) purity be the target compound of 83%.
LC/MS [method 3]: R t=1.49 min; MS [ESIpos]: m/z=566 and 568 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.84 (dd, 1H), 3.90 (s, 3H), 3.99 (dd, 1H), 4.24-4.32 (m, 1H), 5.36-5.47 (m, 2H), 6.85 (d, 1H), 7.33 (d, 1H), 7.38-7.47 (m, 3H), 7.51-7.59 (m, 2H), 7.62 (d, 2H), 7.72 (d, 2H), 8.00 (d, 1H)。
Embodiment 130
3-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-2'-(trifluoromethyl) biphenyl-4-methyl-formiate
With the preparation of embodiment 122 similarly, make 265 mg (0.50 mmol) derive from the compound of embodiment 104A and 149 mg (0.74 mmol) 2-(trifluoromethyl) phenyl-boron dihydroxide reacts.Obtain 113 mg (38% of theoretical value) purity be 100% target compound and 101 mg (28% of theoretical value) purity be the target compound of 81%.
LC/MS [method 3]: R t=1.50 min; MS [ESIpos]: m/z=600 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.90 (s, 3H), 3.97 (dd, 1H), 4.19-4.30 (m, 1H), 5.34-5.47 (m, 2H), 6.83 (d, 1H), 7.16 (s, 1H), 7.37-7.45 (m, 2H), 7.59-7.77 (m, 6H), 7.83 (d, 1H), 7.98 (d, 1H)。
Embodiment 131
The chloro-3-of 2', 3'-bis-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl) biphenyl-4-methyl-formiate
With the preparation of embodiment 75 similarly, make 455 mg (0.85 mmol) derive from compound and 244 mg (1.28 mmol) 2, the 3-dichlorophenyl acid reaction of embodiment 105A.Obtain 347 mg (57% of theoretical value) target compound.
LC/MS [method 4]: R t=1.38 min; MS [ESIpos]: m/z=600 and 602 (M+H) +.
Embodiment 132
The chloro-3-{ of 2'-[3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl } biphenyl-4-carboxylic acid
204 mg (0.36 mmol) are derived from the compound dissolution of embodiment 129 in 3 ml THF, and add 0.4 ml 1 N lithium hydroxide aqueous solution.By described mixture at stirring at room temperature 20 h.In order to carry out aftertreatment, under reduced pressure except desolventizing, resistates being dissolved in about 5 ml water, and adding 0.07 ml 6 N hydrochloric acid.The solid of suction filtration precipitation, and dry.By chromatography on silica gel (elutriant: first use cyclohexane/ethyl acetate 1:3, then by pure ethyl acetate, finally uses methylene chloride/methanol 1:1), be further purified crude product.Obtain 97 mg (47% of theoretical value) target compound.
LC/MS [method 4]: R t=1.20 min; MS [ESIpos]: m/z=552 and 554 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.80 (dd, 1H), 3.99 (dd, 1H), 4.33-4.43 (m, 1H), 5.33-5.44 (m, 1H), 5.49-5.58 (m, 1H), 7.10 (s, 1H), 7.28-7.43 (m, 4H), 7.50-7.55 (m, 1H), 7.60 (d, 2H), 7.71 (d, 2H), 7.74-7.83 (m, 1H)。
Embodiment 133
3-{ [3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl }-2'-(trifluoromethyl) biphenyl-4-carboxylic acid
195 mg (0.36 mmol) are derived from the compound dissolution of embodiment 130 in 3 ml THF, and add 0.4 ml 1 N lithium hydroxide aqueous solution.By described mixture at stirring at room temperature 20 h.In order to carry out aftertreatment, under reduced pressure except desolventizing, resistates being dissolved in about 5 ml water, and adding 0.07 ml 6 N hydrochloric acid.Described mixture is stirred 15 min, then the solid of suction filtration precipitation, and dry under a high vacuum.Obtain 146 mg (73% of theoretical value) target compound.
LC/MS [method 3]: R t=1.38 min; MS [ESIpos]: m/z=586 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.78 (dd, 1H), 3.95 (dd, 1H), 4.31-4.39 (m, 1H), 5.25-5.34 (m, 1H), 5.40-5.47 (m, 1H), 7.02 (s, 1H), 7.24 (d, 1H), 7.37 (d, 1H), 7.56-7.63 (m, 2H), 7.66-7.83 (m, 6H)。
Embodiment 134
The chloro-3-of 2', 3'-bis-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl) biphenyl-4-carboxylic acid
With the preparation of embodiment 132 similarly, react the compound (purity 84%) that 347 mg (0.49 mmol) derive from embodiment 131.Obtain 243 mg (85% of theoretical value) target compound.
LC/MS [method 4]: R t=1.24 min; MS [ESIpos]: m/z=586 and 588 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.84 (dd, 1H), 3.99 (dd, 1H), 4.23-4.31 (m, 1H), 5.40-5.51 (m, 2H), 6.88 (br. s, 1H), 7.24 (s, 1H), 7.33-7.37 (m, 1H), 7.45 (t, 1H), 7.50 (d, 1H), 7.62 (d, 2H), 7.69 (dd, 1H), 7.73 (d, 2H), 8.01 (d, 1H)。
Embodiment 135
The chloro-3-{ of 2'-[3-(4-chloro-phenyl-)-5-oxo-4-(the fluoro-2-hydroxypropyl of 3,3,3-tri-)-4,5-dihydros-1 h-1,2,4-triazol-1-yl] methyl } biphenyl-4-methane amide
The compound that 43 mg (0.08 mmol) derive from embodiment 132 is put into 1 ml DMF in advance, and adds 14 mg (0.10 mmol) HOBt and 19 mg (0.10 mmol) EDC.After stirring at room temperature 10 min, add 0.41 ml (0.20 mmol) ammonia solution (35% in water), and by described mixture at stirring at room temperature 16 h.Then in a vacuum, remove the excess of ammonia in described reaction solution, add about 3 ml water, and with mixture described in each 5 ml extraction into ethyl acetate 3 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography on silica gel (elutriant: cyclohexane/ethyl acetate 1:3 → 1:5) purification of crude product.Obtain 19 mg (42% of theoretical value) target compound.
LC/MS [method 4]: R t=1.14 min; MS [ESIpos]: m/z=551 and 553 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.98 (dd, 1H), 4.24-4.33 (m, 1H), 5.22-5.34 (m, 2H), 6.84 (d, 1H), 7.27 (s, 1H), 7.34-7.47 (m, 4H), 7.52-7.66 (m, 3H), 7.73 (d, 2H), 8.04 (s, 1H)。
Embodiment 136
The chloro-3-of 2', 3'-bis-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl) biphenyl-4-methane amide
The compound that 45 mg (0.07 mmol) derive from embodiment 134 is put into 1 ml DMF in advance, and adds 13 mg (0.09 mmol) HOBt and 18 mg (0.09 mmol) EDC.After stirring at room temperature 10 min, add 80 μ l (1.44 mmol) ammonia solution (35% in water), and by described mixture at stirring at room temperature 16 h.Then in a vacuum, remove the excess of ammonia in described reaction solution, add about 3 ml water, and with mixture described in each 5 ml extraction into ethyl acetate 3 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 20 mg (46% of theoretical value) target compound.
LC/MS [method 3]: R t=1.36 min; MS [ESIpos]: m/z=585 and 587 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.98 (dd, 1H), 4.23-4.32 (m, 1H), 5.22-5.33 (m, 2H), 6.84 (d, 1H), 7.24 (s, 1H), 7.30-7.35 (m, 1H), 7.41-7.47 (m, 2H), 7.56-7.65 (m, 4H), 7.65-7.70 (m, 1H), 7.73 (d, 2H), 8.06 (s, 1H)。
Embodiment 137
5-(4-chloro-phenyl-)-2-{ [the chloro-4-of 2', 3'-bis-(methylol) biphenyl-3-base] methyl }-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-2,4-dihydros-3 h-1,2,4-triazole-3-ketone
230 mg (0.39 mmol) are derived from the compound dissolution of embodiment 134 in 5 ml THF, described solution is cooled to 0 DEG C, and adds 55 μ l (0.39 mmol) triethylamine and 56 μ l (0.43 mmol) isobutyl chlorocarbonate.Described mixture is stirred 1 h at 0 DEG C.Then by match thatch frit, suspension filtered is entered to be cooled in the flask of 0 DEG C, and with about 2 ml THF cleaning and removing residual things.With vigorous stirring, filtrate the adding obtained is cooled in the solution of 44 mg (1.18 mmol) sodium borohydride in 0.6 ml water of 0 DEG C.After 1 h, add 5 ml saturated sodium bicarbonate aqueous solutions, and described mixture is heated to room temperature.With mixture described in 15 ml extraction into ethyl acetate.Successively by saturated sodium bicarbonate solution and the saturated nacl aqueous solution washing organic phase of each 5 ml.After dried over sodium sulfate, filter described mixture, and concentrate in a vacuum.By chromatography [method 19] purification of crude product.Obtain 13 mg (6% of theoretical value) target compound.
LC/MS [method 3]: R t=1.44 min; MS [ESIneg]: m/z=572 (M-H) -
1H-NMR (400 MHz, DMSO-d 6): δ= 3.82 (dd, 1H), 3.98 (dd, 1H), 4.23-4.30 (m, 1H), 4.74 (d, 2H), 5.05-5.15 (m, 2H), 5.30 (t, 1H), 6.86 (d, 1H), 7.27 (d, 1H), 7.33 (dd, 1H), 7.38 (dd, 1H), 7.43 (t, 1H), 7.54 (d, 1H), 7.61 (d, 2H), 7.66 (dd, 1H), 7.70-7.74 (m, 2H)。
Embodiment 138
[the chloro-3-of 2', 3'-bis-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl) biphenyl-4-base] Methyl-carbamic acid ester
65 mg (0.11 mmol) are derived from the compound dissolution of embodiment 137 in 3 ml methylene dichloride, and described mixture is cooled to 0 DEG C.Add 14 μ l (0.16 mmol) Sulfuryl chloride isocyanate, and by described mixture at stirring at room temperature 18 h.Then add 1.5 ml water, and described mixture is stirred other 18 h at 60 DEG C.In order to carry out aftertreatment, add 3 ml saturated sodium bicarbonate aqueous solutions, and with mixture described in each 10 ml extraction into ethyl acetate 2 times.The organic phase merged, through dried over sodium sulfate, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 30 mg (43% of theoretical value) target compound.
LC/MS [method 4]: R t=1.23 min; MS [ESIneg]: m/z=615 and 617 (M-H) -
1H-NMR (400 MHz, DMSO-d 6): δ= 3.82 (dd, 1H), 3.98 (dd, 1H), 4.26-4.33 (m, 1H), 5.08-5.18 (m, 2H), 5.23 (s, 2H), 6.66 (br. s, 2H), 6.86 (d, 1H), 7.32 (d, 1H), 7.34 (dd, 1H), 7.39-7.51 (m, 3H), 7.59-7.64 (m, 2H), 7.67 (dd, 1H), 7.73 (d, 2H)。
Embodiment 139
5-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-2'-(trifluoromethyl) biphenyl-2-methyl-formiate
The compound and 285 mg (0.88 mmol) cesium carbonate that 179 mg (0.58 mmol) are derived from embodiment 5A are suspended in 5 ml acetonitriles, and add the compound that 340 mg (0.58 mmol) derive from embodiment 108A.Described mixture is stirred 4 h under reflux.Then filter out the solid of precipitation, and in a vacuum concentrated filtrate to the volume of about 1.5 ml.After adding 0.5 ml 1 N hydrochloric acid, by chromatography [method 19] directly mixture described in purifying.Obtain 231 mg (65% of theoretical value) target compound.
LC/MS [method 4]: R t=1.26 min; MS [ESIpos]: m/z=600 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.52 (s, 3H), 3.84 (dd, 1H), 3.99 (dd, 1H), 4.25-4.32 (m, 1H), 5.03-5.18 (m, 2H), 6.88 (dd, 1H), 7.21-7.29 (m, 2H), 7.46 (d, 1H), 7.55-7.69 (m, 4H), 7.70-7.75 (m, 2H), 7.77 (d, 1H), 7.97 (d, 1H)。
Embodiment 140
The chloro-5-of 2'-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl) biphenyl-2-methyl-formiate
With the preparation of embodiment 139 similarly, 208 mg (0.68 mmol) are derived from, and compound that the compound of embodiment 5A and 230 mg (0.68 mmol) derive from embodiment 109A reacts.Obtain 231 mg (59% of theoretical value) target compound.
LC/MS [method 4]: R t=1.26 min; MS [ESIpos]: m/z=566 and 568 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.58 (s, 3H), 3.84 (dd, 1H), 4.02 (dd, 1H), 4.26-4.33 (m, 1H), 5.07-5.18 (m, 2H), 6.88 (d, 1H), 7.25-7.31 (m, 2H), 7.36-7.52 (m, 4H), 7.62 (d, 2H), 7.74 (d, 2H), 7.93 (d, 1H)。
Embodiment 141
5-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-2'-(trifluoromethyl) diphenyl-2-carboxylic acid
215 mg (0.36 mmol) are derived from the compound dissolution of embodiment 139 in 3 ml THF and 3 ml methyl alcohol, and add 0.36 ml 2 N aqueous sodium hydroxide solution.Described mixture is stirred 16 h at 80 DEG C.In order to carry out aftertreatment, dilute described mixture with 10 ml water, and with each 10 ml extraction into ethyl acetate 2 times.With 1 N hcl acidifying aqueous phase, and again extract 1 time by 10 ml ethyl acetate.Merge organic phase, through dried over mgso, filter, and concentrate in a vacuum.Dried residue under a high vacuum.Obtain the target compound of 222 mg (quantitatively).
LC/MS [method 3]: R t=1.29 min; MS [ESIpos]: m/z=586 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.84 (dd, 1H), 3.98 (dd, 1H), 4.24-4.31 (m, 1H), 5.02-5.16 (m, 2H), 6.88 (dd, 1H), 7.19 (br. s, 1H), 7.26 (d, 1H), 7.43 (d, 1H), 7.56 (t, 1H), 7.59-7.67 (m, 3H), 7.69-7.77 (m, 3H), 7.96 (d, 1H), 12.59 (br. s, 1H)。
Embodiment 142
The chloro-5-of 2'-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl) diphenyl-2-carboxylic acid
With the preparation of embodiment 141 similarly, make 218 mg (0.39 mmol) derive from the compound of embodiment 140 and 2 N aqueous sodium hydroxide solutions react.Obtain 220 mg (quantitatively) target compound.
LC/MS [method 3]: R t=1.26 min; MS [ESIpos]: m/z=552 and 554 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.84 (dd, 1H), 4.00 (dd, 1H), 4.24-4.35 (m, 1H), 5.05-5.16 (m, 2H), 6.89 (d, 1H), 7.24 (s, 1H), 7.25-7.30 (m, 1H), 7.34-7.39 (m, 2H), 7.42 (dd, 1H), 7.45-7.50 (m, 1H), 7.59-7.65 (m, 2H), 7.72-7.77 (m, 2H), 7.92 (d, 1H), 12.64 (br. s, 1H)。
Embodiment 143
5-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-2'-(trifluoromethyl) biphenyl-2-methane amide
The compound that 208 mg (0.36 mmol) derive from embodiment 141 is put into 5 ml DMF in advance, and adds 62 mg (0.46 mmol) HOBt and 88 mg (0.46 mmol) EDC.After stirring at room temperature 10 min, add 1.0 ml (16 mmol) ammonia solution (33% in water), and by described mixture at stirring at room temperature 16 h.Then in a vacuum, remove the excess of ammonia in described reaction solution, add about 3 ml water, and with mixture described in each 5 ml extraction into ethyl acetate 3 times.The organic phase merged, through dried over mgso, is filtered, and is concentrated in a vacuum.By chromatography [method 19] purification of crude product.Obtain 85 mg (39% of theoretical value) target compound.
LC/MS [method 2]: R t=2.29 min; MS [ESIpos]: m/z=585 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.99 (dd, 1H), 4.24-4.31 (m, 1H), 4.98-5.12 (m, 2H), 6.87 (d, 1H), 7.08-7.18 (m, 2H), 7.29 (d, 1H), 7.37 (d, 1H), 7.50-7.65 (m, 6H), 7.67-7.76 (m, 3H)。
Embodiment 144
The chloro-5-of 2'-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl) biphenyl-2-methane amide
With the preparation of embodiment 143 similarly, make 210 mg (0.38 mmol) derive from the compound of embodiment 142 and ammonia solution reacts.Obtain 122 mg (54% of theoretical value) target compound.
LC/MS [method 4]: R t=1.06 min; MS [ESIpos]: m/z=551 and 553 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.84 (dd, 1H), 4.00 (dd, 1H), 4.24-4.35 (m, 1H), 5.01-5.12 (m, 2H), 6.88 (d, 1H), 7.17 (s, 1H), 7.23 (d, 1H), 7.26-7.31 (m, 1H), 7.31-7.39 (m, 3H), 7.44-7.49 (m, 1H), 7.52-7.59 (m, 2H), 7.62 (d, 2H), 7.74 (d, 2H)。
Embodiment 145
n-the tertiary butyl-5-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl)-2'-(trifluoromethyl) biphenyl-2-methane amide
The compound that 30 mg (0.05 mmol) derive from embodiment 141 is put into 0.75 ml DMF in advance, and adds 9 mg (0.074 mmol) HOBt and 13 mg (0.07 mmol) EDC.After stirring at room temperature 10 min, add 6 μ l (0.06 mmol) 2-methylpropane-2-amine, and by described mixture at stirring at room temperature 16 h.Then 50 μ l 1 N hydrochloric acid are added, and by chromatography [method 19] directly mixture described in purifying.Obtain 8.2 mg (24% of theoretical value) target compound.
LC/MS [method 2]: R t=2.70 min; MS [ESIpos]: m/z=641 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 1.08 (s, 9H), 3.84 (dd, 1H), 3.99 (dd, 1H), 4.24-4.35 (m, 1H), 4.99-5.11 (m, 2H), 6.88 (d, 1H), 7.17 (d, 1H), 7.25 (s, 1H), 7.38 (t, 2H), 7.48 (d, 1H), 7.54-7.67 (m, 4H), 7.71 (d, 2H), 7.78 (d, 1H)。
Embodiment 146
The chloro-5-of 2'-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl) biphenyl-3-methyl-formiate
With the preparation of embodiment 139 similarly, 248 mg (0.81 mmol) are derived from, and compound that the compound of embodiment 5A and 274 mg (0.81 mmol) derive from embodiment 112A reacts.Obtain 271 mg (59% of theoretical value) target compound.
LC/MS [method 3]: R t=1.48 min; MS [ESIpos]: m/z=566 and 568 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.84 (dd, 1H), 3.87 (s, 3H), 4.01 (dd, 1H), 4.23-4.33 (m, 1H), 5.10-5.21 (m, 2H), 6.87 (s, 1H), 7.42-7.48 (m, 3H), 7.58-7.65 (m, 3H), 7.68-7.76 (m, 3H), 7.93 (s, 1H), 7.99 (s, 1H)。
Embodiment 147
The chloro-5-of 2'-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl) biphenyl-3-carboxylic acid
With the preparation of embodiment 141 similarly, make 244 mg (0.43 mmol) derive from the compound of embodiment 146 and 2 N aqueous sodium hydroxide solutions react.Obtain 242 mg (100% theoretical value) target compound.
LC/MS [method 3]: R t=1.33 min; MS [ESIpos]: m/z=552 and 554 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.98-4.04 (m, 1H), 4.29-4.35 (m, 1H), 5.04-5.14 (m, 2H), 7.36-7.48 (m, 5H), 7.57 (d, 1H), 7.61 (d, 2H), 7.74 (d, 2H), 7.87 (br. s, 1H)。
Embodiment 148
The chloro-5-of 2'-({ 3-(4-chloro-phenyl-)-5-oxo-4-[(2 s)-3,3,3-tri-fluoro-2-hydroxypropyls]-4,5-dihydros-1 h-1,2,4-triazol-1-yl } methyl) biphenyl-3-methane amide
With the preparation of embodiment 143 similarly, make 55 mg (0.10 mmol) derive from the compound of embodiment 147 and ammonia solution reacts.Obtain 25 mg (43% of theoretical value) target compound.
LC/MS [method 4]: R t=1.12 min; MS [ESIpos]: m/z=551 and 553 (M+H) +
1H-NMR (400 MHz, DMSO-d 6): δ= 3.83 (dd, 1H), 3.96-4.03 (m, 1H), 4.26-4.33 (m, 1H), 5.05-5.16 (m, 2H), 6.52 (s, 1H), 6.89 (d, 1H), 7.41-7.49 (m, 4H), 7.55-7.65 (m, 3H), 7.74 (d, 2H), 7.88 (d, 2H), 8.06 (s, 1H)。
B. the evaluation of pharmacological activity
The pharmacotoxicological effect according to compound of the present invention can be confirmed in following test:
Abbreviation:
EDTA ethylenediamine tetraacetic acid (EDTA)
The Eagle substratum that DMEM DulbeccoShi improves
FCS foetal calf serum
HEPES 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid
SmGM smooth muscle cell growth substratum
Tris-HCl 2-amino-2-(methylol)-1,3-PD hydrochloride.
B-1. for measuring the cells in vitro test of vasopressin receptor activity
By means of recombinant cell lines, carry out the agonist of V1a-and V2-vasopressin receptor and the discriminating of antagonist of the mankind and rat, and quantitative according to the activity of compound of the present invention.These cells derive from Hamster Qvary epithelial cell (Chinese hamster ovary, CHO K1, ATCC: American type culture collection, Manassas, VA 20108, USA) at first.Described experimental cell system expresses the modification of calcium sensitive luminescent protein aequorin fatefully, described luminescent protein is after reconstructing by cofactor coelenterazine (Coelenterazine), utilizing emitted light [the Rizzuto R when free calcium concentration increases, Simpson AW, Brini M, Pozzan T nature 358, 325-327 (1992)].In addition, V1a-or the V2-acceptor of employment or rat stably cell described in transfection.When the V2-acceptor of coupling Gs, with another gene independently or as fusion gene stably cell described in transfection, the G of described genes encoding polygamy α 16albumen [Amatruda TT, Steele DA, Slepak VZ, Simon MI, proceedings in the National Academy of Science USA 88, 5587-5591 (1991)].The vasopressin receptor experimental cell obtained makes response to the stimulation discharging the recombinant expressed vasopressin receptor caused in the cell of calcium ion, this can use suitable photometer to quantize [Milligan G by the aequorin luminescence obtained, Marshall F, Rees S trends in Pharmacological Sciences 17, 235-237 (1996)].
experimentation:
1 day before the test, by the substratum of described plating cells in the microwell plate of 384-hole (DMEM, 10% FCS, 2 mM glutamine, 10 mM HEPES), and remain on cell culture incubator (96% atmospheric moisture, 5% v/v CO 2, 37 DEG C) in.Testing the same day, by Tyrode solution (140 mM NaCl, 5 mM KCl, 1 mM MgCl 2, 2 mM CaCl 2, 20 mM glucose, 20 mM HEPES) replace substratum, described Tyrode solution in addition containing cofactor coelenterazine (50 μm), then by the other 3-4 hour of described microwell plate incubation.Experiment thing is placed 10-20 minute with different concentration in the hole of microwell plate, then adds agonist [Arg 8]-vassopressin, and the optical signal measuring generation immediately in photometer.Use computer program GraphPad PRISM (3.02 editions), calculate IC 50value.
The representational IC of compound according to the present invention to the clone of V1a-or the V2-acceptor transfection of employment is listed in following table 50value:
table
B-2. for detecting vassopressin V1a receptor antagonist, the cells in vitro of the regulating effect of short fibrosis gene is tested
Isolated from rat cardiac tissue, to be described to cardiac myocyte cell type (American type culture collection ATCC CRL-1446) clone H9C2 with high copy number endogenous express vassopressin V1A acceptor AVPR1A, and can not detect that AVPR2 expresses.Carry out the test cell line regulated by the AVPR1A receptor-independent of receptor antagonist inhibition of gene expression as follows:
For in the 12-hole microwell plate of cell cultures, with the cell density of 100000 cells/well, H9C2 cell is seeded in 1.0 ml Opti-MEM substratum (Invitrogen Corp., Carlsbad CA, USA, catalog number (Cat.No.) 11058-021) in, described substratum contains 2% FCS and 1% penicillin/streptomycin solution (Invitrogen, catalog number (Cat.No.) 10378-016), and remain in cell culture incubator (96% atmospheric moisture, 5% v/v carbonic acid gas, 37oC).After 24 hours, add vehicle solution (negative control), vassopressin solution ([Arg to often group 3 holes (in triplicate) 8]-vassopressin acetic ester, Sigma, catalog number (Cat.No.) V9879) or Test Materials (being dissolved in the vehicle aqueous solution containing 20 volume % ethanol) and vassopressin solution.In cell cultures, final vasopressin concentrations is 0.05 μM.Test Materials solution is added in cell culture with small volume, to such an extent as in test cell line, is no more than the ethanol final concentration of 0.1%.After the incubative time of 6 hours, pump out culture supernatants, make the cell of adhesion at 250 μ l RLT damping fluid (Qiagen, Ratingen, catalog number (Cat.No.) 79216) middle cracking, and use RNeasy test kit (Qiagen, catalog number (Cat.No.) 74104) to isolate RNA from this lysate.Dnase digestion (Invitrogen is carried out after this, catalog number (Cat.No.) 18068-015), cDNA synthesizes (ImProm-II reverse transcription system, Promaga, catalog number (Cat.No.) A3800) and RTPCR (pPCR MasterMix RT-QP2X-03-075, Eurogentec, Seraing, Belgium).The experimentally programme of work of the manufacturer of reagent, carries out all operations.By means of program Primer3Plus, the probe marked with 6-FAM TAMRA-, based on mRNA gene order (NCBI Genbank Entrez RiboaptDB), selects the primer set of RTPCR.Use Applied Biosystems ABI Prism 7700 sequential detector, according to instrumentation specification sheets, the RTPCR of mrna expression relatively in the cell carrying out for being determined at different tests batch with 96-hole-or 384-hole microwell plate formula.The expression intensity of reference gene ribosomal protein L-32 (Genbank registration number NM_013226) and the Ct threshold value of Ct=35, with δ-δ Ct value [Applied Biosystems, No. 2 user's bulletin, ABI Prism 7700 SDS, on December 11st, 1997 (renewal in October calendar year 2001)] represent that Relative gene is expressed.
B-3. for detecting the in vivo test of cardiovascular effect: the blood pressure measurement of the rat of anesthesia (vassopressin ' challenge model)
With ketamine/xylazine/Sodital injecting anesthetic; in male Sprague-Dawley rat (250-350 g body weight), the polyethylene tube (PE-50 of the isotonic sodium chlorrde solution containing heparin (500 I.E./ml) will be pre-installed; Intramedic) insert in jugular vein and femoral vein, then fix.Via a venous inlet, with injector to inject Arg-vassopressin; Via second venous inlet, use Test Materials.In order to measure systolic blood pressure, catheter pressure (Millar SPR-320 2F) is fixed in carotid artery.Be connected on pressure receptor by described ductus arteriosus, its signal is delivered to the metering computer of being furnished with suitable logging software by described pressure receptor.In a model experiment, with the interval of 10-15 min, the continuous bolus injection of 3-4 the Arg-vassopressin (30 ng/kg) containing the determined amounts in isotonic sodium chlorrde solution is used to laboratory animal, when blood pressure reaches initial value again, in a suitable solvent, use Test Materials as bolus injection, carry out continuous infusion subsequently.After this, at the interval determined (10-15 min), again use and the Arg-vassopressin starting identical amount.Based on pressure value, determination experiment material offsets the degree of Arg-vassopressin raising blood pressure effect.Control animal only obtains solvent and substitutes experiment thing.
After intravenous administration, compared with solvent control, compound according to the present invention plays the effect suppressing the elevation of blood pressure caused by Arg-vassopressin.
B-4. for detecting the in vivo test of cardiovascular effect: study the diuresis of Conscious Rat in metabolic cage
Keep Wistar rat (300-450 g body weight) freely close to feed (Altromin) and tap water.At experimental session, in the metabolic cage being applicable to this heavyweight rat, individually maintain animal freely close to tap water 4-8 hour (Tecniplast Deutschland GmbH, D-82383 Hohenpei enberg).When testing beginning, by means of gavage, with the suitable solvent volume of 1-3 ml/kg body weight, material to be detected is used in the stomach of precession thing.Control animal only accepts solvent.On the same day, carry out abreast contrasting and test thing experiment.Control group and dosages of substance group are respectively made up of 4-8 animal.At experimental session, the urine that animal drains is collected in the receptor being arranged in cage bottom continuously.For every animal, measure the urine volume in time per unit individually, by the standard method of flame photometry, measure the concentration of the excretion sodium in urine-and potassium ion.In order to obtain enough urine volume, used the water (usual 10 ml/kg body weight) of determined amounts to animal by gavage when testing beginning.After terminating with experiment before experiment starts, measure the body weight of each animal.
After oral administration, compared with using with solvent control, compound according to the present invention causes homaluria to increase, and this is mainly based on water excretion (Li Shui effect) increased.
B-5. for detecting the in vivo test of cardiovascular effect: to the Hemodynamics research of the dog of anesthesia
Use Sodital (30 mg/kg intravenouslys respectively, Narcoren, Merial, Germany) the male or female mongrel (Mongrels of anesthesia body weight between 20-30 kg, Marshall BioResources, USA), for surgical operation and Hemodynamics and functional study object.Use alcuronium chloride (3 mg/ animals, intravenously, Alloferin, ICN Pharmaceuticals, Germany) as muscle relaxant in addition at this.Insert trunnion to described dog, and ventilate with oxygen/ambient air mixture (40/60%, about 5-6 L/min).Use derives from the respirator of Draeger (Sulla 808), ventilates, and uses capnograph (Engstr m) to monitor.By continuous infusion Sodital (50 μ g/kg/min), maintain anesthesia; Use fentanyl as pain killer (10 μ g/kg/h).It is use isoflurane (1-2 volume %) that the one of Sodital substitutes.
In preparatory intervention, implant a pacemaker to described dog.In the drug test (=experiment starts) time of 21 days before first time, by schrittmacher (Biotronik, Logos) implant in subcutaneous leather bag, and be connected with heart via pacemaker electrode, described pacemaker electrode is extended in right ventricle by external jugular vein.
While implantable pacemaker, by 7F examination of living tissue pliers (Cordis) via the cover tube inserter (Avanti+ in femoral artery; Cordis) fall back mobile and at hurtless measure through after aortic valve, under cardiography and perspective monitoring, determine mitral damage.After this, take out total interface, described dog is naturally clear-headed from anesthesia.After other 7 days (=before first time drug test 14 days), activate above-mentioned pacemaker, and beating for 220 times/minute frequency stimulation heart.
After beginning pacemaker stimulates 14 and 28 days, use following instrument, start actual drug test experiment:
● insert bladder catheter, for releiving bladder and for measuring urine flow;
● electrocardiogram(ECG (EKG) wire is connected to four limbs, measures for EKG;
● the Fluidmedic of sodium chloride solution will be housed ?pE-300 pipe inserts in femoral artery, this pipe is connected to pressure receptor (Braun Melsungen, Germany), for measuring systemic blood pressure;
● through left atrium or through being arranged on the port in carotid artery, insert Millar Tip conduit (350 PC types, Millar Instruments, Houston, USA), for measuring cardiac hemodynamics
● via jugular vein, Swan-Ganz conduit (CCOmbo 7.5F, Edwards, Irvine, USA) is inserted in pulmonary artery, for measuring cardiac output, oxygen saturation, Ppa pulmonary artery pressure and central venous pressure
● ductus venosus is put into cephalic vein, for infusion Sodital, for liquid replacement with for blood sampling (for measuring blood plasma level or other clinical blood value of material)
● ductus venosus is put into saphena, for infusion fentanyl with for application of substances
● with the dose infusion vassopressin (Sigma) increased progressively, until the dosage of 4 mU/kg/min.Then pharmacological agents is tested at this dose.
If necessary, amplify primary signal (Gould amplifier, Gould Instrument Systems, Valley View, USA or Edwards-Vigilance-Monitor, Edwards, Irvine, USA), input Ponemah system (DataSciences Inc subsequently, Minneapolis, USA) for evaluating.Recording signal continuously in the whole experimental phase, and digitally processed further by described software, get the mean value in 30 seconds.
C. the embodiment of pharmaceutical composition
Pharmaceutical preparation can be changed in the following manner according to compound of the present invention:
tablet:
composition:
100 mg according to compound of the present invention, 50 mg lactose (monohydrate), 50 mg W-Gums (natural), 10 mg polyvinylpyrrolidones (PVP 25) (derive from BASF, Ludwigshafen, Germany), and 2 mg Magnesium Stearates.
Tablet weight 212 mg, diameter 8 mm, radius-of-curvature 12 mm.
produce:
Use the solution of PVP in water (m/m) of 5%, by the mixture pelleting of compound according to the present invention, newborn sugar and starch.After drying, this particle is mixed 5 minutes with Magnesium Stearate.This mixture (about the form of tablet, see above) is suppressed with conventional tablet presses.Standard value for suppressing uses the pressure of 15 kN.
suspension that can be Orally administered:
composition:
1000 mg according to compound of the present invention, 1000 mg ethanol (96%), 400 mg Rhodigel (xanthan gum derives from FMC, Pennsylvania, USA), and 99 g water.
10 ml oral administration mixed suspensions are equivalent to the single dose of 100 mg according to compound of the present invention.
produce:
Rhodigel is suspended in ethanol, compound according to the present invention is added in described suspension.Under agitation, water is added.By described mixture stir about 6 h, until the swelling end of Rhodigel.
solution that can be Orally administered:
composition:
500 mg according to compound of the present invention, 2.5 g polysorbates, and 97 g poly(oxyethylene glycol) 400.20 g oral liquids are equivalent to the single dose of 100 mg according to compound of the present invention.
produce:
Under agitation, compound according to the present invention is suspended in the mixture of polyoxyethylene glycol and polysorbate.Whipping process continues to compound according to the present invention and dissolves completely.
intravenous solution:
With the concentration lower than the saturation solubility in the solvent tolerated on physiology (such as isotonic saline solution, 5% glucose solution and/or 30% PEG 400 solution), dissolve according to compound of the present invention.By filtering, described solution sterilization is filtered, and be filled in aseptic and in pyrogen-free injection vessel.

Claims (9)

1. the compound of formula (I) and their salt
Wherein
R 1represent (C 1-C 6)-alkyl, it can be selected from following identical or different residue Dan Zhisan and replace: fluorine, trifluoromethyl, oxo, hydroxyl, methoxyl group, oxyethyl group, (C 3-C 6)-cycloalkyl and phenyl,
Wherein (C 3-C 6)-cycloalkyl can be selected from following identical or different residue and replace maximum 2 times: fluorine, methyl, trifluoromethyl, ethyl and hydroxyl
And
Wherein phenyl can be selected from maximum 2 times of following identical or different residue replacement: fluorine, chlorine, cyano group, methyl, difluoromethyl, trifluoromethyl, ethyl, hydroxyl, methoxyl group, trifluoromethoxy, oxyethyl group, hydroxycarbonyl group, methoxycarbonyl, ethoxy carbonyl and aminocarboxyl
Or
Represent (C 2-C 6)-thiazolinyl
Or
Represent (C 3-C 6)-cycloalkyl, it can be selected from following identical or different residue list or two replacements: fluorine, methyl, trifluoromethyl, ethyl and hydroxyl,
Ar 1represent phenyl or thienyl, they can be selected from following identical or different residue list or two replacements separately: fluorine, chlorine, cyano group, methyl, trifluoromethyl, ethyl, hydroxyl, methoxyl group, trifluoromethoxy and oxyethyl group,
L 1represent group-CH 2-or-SO 2-,
Q represents that having maximum 3 is selected from ring-heteroatomic 5 yuan of heteroaryl rings of N, O and/or S or has 6 yuan of heteroaryl rings of maximum 2 ring-nitrogen-atoms, or
Q represents the optional following formula benzyl ring replaced
Wherein
* represent and group L 1link position,
* represents and group L 2link position,
R 2Arepresent hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, hydroxymethyl, carbamoyloxy group methyl, hydroxycarbonyl group, methoxycarbonyl, ethoxy carbonyl, aminocarboxyl, methylaminocarbonyl or tert-butylamino carbonyl,
R 2represent and be selected from following substituting group: fluorine, chlorine, bromine, (C 1-C 4)-alkyl, (C 3-C 6)-cycloalkyl, phenyl, (C 1-C 4)-alkoxyl group, hydroxycarbonyl group, (C 1-C 4)-alkoxy carbonyl, aminocarboxyl and list-(C 1-C 4)-alkyl amino-carbonyl,
Wherein with regard to described (C 1-C 4)-alkyl substituent, can by hydroxyl, (C 1-C 4)-alkoxyl group, carbamoyloxy group, hydroxycarbonyl group, (C 1-C 4)-alkoxy carbonyl or aminocarboxyl replace, or replaced by fluorine maximum 3 times
And
Wherein with regard to described phenyl substituent, can be replaced by fluorine, chlorine, methyl or trifluoromethyl,
N representative digit 0 or 1,
L 2represent key or expression-(CR 3Ar 3B) p-group, wherein
R 3Arepresent hydrogen or methyl,
R 3Brepresent hydrogen, (C 1-C 4)-alkyl, hydroxycarbonyl group, (C 1-C 4)-alkoxy carbonyl or aminocarboxyl,
Wherein (C 1-C 4)-alkyl can be replaced by hydroxyl or carbamoyloxy group,
And
P representative digit 1 or 2,
Wherein at group-CR 3Ar 3B-occur 2 times when, R 3Aand R 3Bimplication respective in each case can be identical or different,
And
Ar 2represent phenyl, it can be selected from following identical or different residue list or two replacements: fluorine, chlorine, cyano group, difluoromethyl, trifluoromethyl, (C 1-C 4)-alkyl, methoxyl group, difluoro-methoxy, trifluoromethoxy and oxyethyl group.
2. formula according to claim 1 (I) compound and their salt, wherein
R 1represent (C 1-C 4)-alkyl, it can be selected from following identical or different residue list or two replacements: fluorine, trifluoromethyl, oxo, hydroxyl and phenyl,
Wherein with regard to described phenyl substituent, following group can be selected from and replace: fluorine, chlorine, methyl, trifluoromethyl, methoxyl group, hydroxycarbonyl group and methoxycarbonyl,
Or
Represent allyl group or cyclopropyl,
Ar 1represent phenyl or thienyl, each in them is selected from following group replacement: fluorine and chlorine,
L 1represent group-CH 2-,
Q represents the pyridyl ring of following formula, pyrimidine-ring or the optional benzyl ring replaced
Or
Represent 5 yuan of heteroaryl rings of following formula
Wherein
* represent and group L 1link position,
And
* represents and group L 2link position,
R 2Arepresent hydrogen, fluorine, chlorine, bromine, methyl, trifluoromethyl, hydroxymethyl, carbamoyloxy group methyl, hydroxycarbonyl group, methoxycarbonyl, ethoxy carbonyl, aminocarboxyl, methylaminocarbonyl or tert-butylamino carbonyl,
R 2Brepresent hydrogen, methyl or trifluoromethyl
And
R 2Crepresent hydrogen or methyl, described methyl can be replaced by hydroxycarbonyl group, methoxycarbonyl or aminocarboxyl,
L 2represent key or group-CH 2-
And
Ar 2represent phenyl, described phenyl is selected from following identical or different residue list or two replacements: fluorine, chlorine, methyl, trifluoromethyl, methoxyl group and trifluoromethoxy.
3. according to formula (I) compound and their salt of claim 1 or 2, wherein
R 1represent (C 1-C 4)-alkyl, it can be selected from following identical or different residue list or two replacements: fluorine, trifluoromethyl and hydroxyl, or representative ring propyl group,
Ar 1represent rubigan,
L 1represent group-CH 2-,
Q represents the pyrimidine-ring of following formula
Or
Represent 5 yuan of heteroaryl rings of following formula
Wherein
* represent and group L 1link position,
And
* represents and group L 2link position,
R 2Brepresent hydrogen, methyl or trifluoromethyl
And
R 2Crepresent hydrogen or methyl, described methyl can be replaced by hydroxycarbonyl group, methoxycarbonyl or aminocarboxyl,
L 2represent key or group-CH 2-
And
Ar 2represent phenyl, described phenyl is selected from following identical or different residue list or two replacements: fluorine, chlorine, methyl, trifluoromethyl, methoxyl group and trifluoromethoxy.
4., for the preparation of the method for the formula defined in any one of claim 1-3 (I) compound, it is characterized in that,
In the presence of a base, 5-aryl-1,2, the 4-triazolone derivative of formula (II) is made
Wherein Ar 1and R 1there is the implication provided in any one of claim 1-3,
[A] and formula (III) compound react
Wherein Ar 2, L 1, L 2, Q, R 2with n, there is the implication provided in any one of claim 1-3,
And
X 1represent leavings group, be selected from chlorine, bromine, iodine, methanesulfonates or tosylate,
Obtain formula (I) compound
Or
[B] in a replacement scheme, the L in formula (I) 2represent key and group Ar 2when being connected with the carbon atom of ring Q,
React with formula (IV) compound
Wherein L 1, Q, R 2with n, there is the implication provided in any one of claim 1-3,
X 1represent leavings group, be selected from chlorine, bromine, iodine, methanesulfonates or tosylate
And
X 2represent the leavings group be connected with the carbon atom of ring Q, be selected from chlorine, bromine, iodine, methanesulfonates or trifluoromethane sulfonic acid ester, obtain formula (V) intermediate
Wherein Ar 1, L 1, Q, R 1, R 2, X 2with n, there is the implication provided above,
Then, under suitable transition-metal catalyst exists, itself and the coupling of formula (VI) compound is made,
Ar 2-M (VI)，
Wherein Ar 2there is the implication provided in any one of claim 1-3,
And
M represents the group of following formula :-B (OR 4) 2,-MgHal ,-ZnHal or-Sn (R 5) 3, wherein
Hal represents chlorine, bromine or iodine,
R 4represent hydrogen or (C 1-C 4)-alkyl, or two residue R 4be connected with each other and common formation-(CH 2) 2-,-(CH 2) 3-,-C (CH 3) 2-C (CH 3) 2-or-CH 2-C (CH 3) 2-CH 2-bridge
And
R 5represent (C 1-C 4)-alkyl,
Obtain formula (I-A) compound
Wherein Ar 1, Ar 2, L 1, Q, R 1, R 2with n, there is the implication provided above,
Or
[C] in a replacement scheme, the L in formula (I) 2represent the group-(CR defined in any one of claim 1-3 3Ar 3B) p-and when being connected with the nitrogen-atoms of ring Q,
React with formula (VII) compound
Wherein L 1, R 2with n, there is the implication provided in any one of claim 1-3,
At the undefined 5 yuan of heteroaryl rings of Q in any one of Q ' expression claim 1-3, it contains the trivalent ring-nitrogen-atoms be connected with the hydrogen atom of instruction,
And
X 1represent leavings group, be selected from chlorine, bromine, iodine, methanesulfonates or tosylate,
Obtain the intermediate of formula (VIII)
Wherein Ar 1, L 1, Q ', R 1, R 2with n, there is the implication provided above,
Then in the presence of a base, with formula (IX) compound by its N-alkylation
Wherein Ar 2there is the implication provided in any one of claim 1-3,
L 2Arepresent the group-(CR defined in any one of claim 1-3 3Ar 3B) p-,
And
X 3represent leavings group, be selected from chlorine, bromine, iodine, methanesulfonates or tosylate,
Obtain formula (I-B) compound
Wherein Ar 1, Ar 2, L 1, L 2A, Q ', R 1, R 2with n, there is the implication provided above,
And optionally the compound separation of the formula so obtained (I), (I-A) or (I-B) is become their enantiomer and/or diastereomer, and/or change into their salt with suitable alkali or acid.
5. formula (I) compound defined in any one of claim 1-3 for the preparation of the purposes of medicine, the disease that described medicine is used for the treatment of and/or prevents vassopressin to cause.
6. formula (I) compound defined in any one of claim 1-3 is for the preparation of the purposes of medicine, and described medicine is used for the treatment of and/or prevents acute and chronic heart failure, hypervolemic and the normal hyponatremia of Q volume of blood, liver cirrhosis, ascites, oedema and ADH hyposecretion syndrome (SIADH).
7. comprise the medicine of formula (I) compound that in any one of claim 1-3 define combined with one or more inertia, nontoxic, pharmaceutically suitable vehicle.
8. comprise the medicine of formula (I) compound that in any one of claim 1-3 define combined with one or more other active substances, other active substance described is selected from: diuretic(s), Angiotensin AII antagonist, ACE inhibitor, beta-blocker, mineralocorticoid receptor antagonists, organic nitrate, NO donor and positivity variable force active substance.
9., according to the medicine of claim 7 or 8, described medicine is used for the treatment of and/or prevents acute and chronic heart failure, hypervolemic and the normal hyponatremia of Q volume of blood, liver cirrhosis, ascites, oedema and ADH hyposecretion syndrome (SIADH).
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